U.S. patent application number 15/107374 was filed with the patent office on 2017-01-05 for benzene sulfonamides as ccr9 inhibitors.
This patent application is currently assigned to Norgine B.V.. The applicant listed for this patent is NORGINE B.V.. Invention is credited to Rajagopal Bakthavatchalam, Manas Kumar Basu, Ajit Kumar Behera, Akila Parvathy Dharshinis, Christopher Alexander Hewson, Sanjay Venkatachalapathi Kadnur, Sarkis Barret Kalindjian, Rajenda Kristam, Bheemashankar Kulkarni, Rohit Saxena, Juluri Suresh, Chandregowda Venkateshappa, Vellarkad Viswanathan, Mohd Zainuddin.
Application Number | 20170002011 15/107374 |
Document ID | / |
Family ID | 52232192 |
Filed Date | 2017-01-05 |
United States Patent
Application |
20170002011 |
Kind Code |
A1 |
Bakthavatchalam; Rajagopal ;
et al. |
January 5, 2017 |
BENZENE SULFONAMIDES AS CCR9 INHIBITORS
Abstract
The present invention relates to compounds useful as CCR9
modulators, to compositions containing them, to methods of making
them, and to methods of using them. In particular, the present
invention relates to compounds capable of modulating the function
of the CCR9 receptor by acting as partial agonists, antagonists or
inverse agonists. Such compounds may be useful to treat, prevent or
ameliorate a disease or condition associated with CCR9 activation,
including inflammatory and immune disorder diseases or conditions
such as inflammatory bowel diseases (IBD). ##STR00001##
Inventors: |
Bakthavatchalam; Rajagopal;
(Bangalore, IN) ; Basu; Manas Kumar; (Ghaziabad,
Uttar Pradesh, IN) ; Behera; Ajit Kumar;
(Dist-nayagarth, Orissa, IN) ; Venkateshappa;
Chandregowda; (Bangalore, IN) ; Hewson; Christopher
Alexander; (Middlesex, GB) ; Kadnur; Sanjay
Venkatachalapathi; (Bangalore, IN) ; Kalindjian;
Sarkis Barret; (Middlesex, GB) ; Kulkarni;
Bheemashankar; (Bangalore, IN) ; Saxena; Rohit;
(Lucknow, Uttar Pradesh, IN) ; Suresh; Juluri;
(Hyderabad, Andhra Pradesh, IN) ; Viswanathan;
Vellarkad; (Bangalore, Karnataka, IN) ; Zainuddin;
Mohd; (Kanpur, Uttar Pradesh, IN) ; Dharshinis; Akila
Parvathy; (Thruneveli, Tamil Nadu, IN) ; Kristam;
Rajenda; (Bangalore, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NORGINE B.V. |
Amsterdam Zuid-Ost |
|
NL |
|
|
Assignee: |
Norgine B.V.
Amsterdam Zuid-Ost
NL
|
Family ID: |
52232192 |
Appl. No.: |
15/107374 |
Filed: |
December 22, 2014 |
PCT Filed: |
December 22, 2014 |
PCT NO: |
PCT/EP2014/078945 |
371 Date: |
June 22, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/04 20180101; C07D
487/04 20130101; C07D 471/04 20130101; A61P 29/00 20180101; A61P
37/02 20180101; A61P 37/00 20180101; A61P 43/00 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 471/04 20060101 C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 2013 |
IN |
5985/CHE/2013 |
Claims
1. A compound of Formula (I) or a salt or solvate thereof,
including a solvate of such a salt: ##STR00569## in which: each
R.sub.1 is Z.sub.q1B; m is 0, 1,2 or 3; q.sub.1 is 0, 1, 2, 3, 4, 5
or 6; each Z is independently selected from CR.sub.5R.sub.6, O,
C.dbd.O, SO.sub.2, and NR.sub.7; each R.sub.5 is independently
selected from hydrogen, methyl, ethyl, and halo; each R.sub.6 is
independently selected from hydrogen, methyl, ethyl, and halo; each
R.sub.7 is independently selected from hydrogen, methyl, and ethyl;
each B is independently selected from hydrogen, halo, cyano (CN),
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, and A; A is ##STR00570## Q is
selected from CH.sub.2, O, NH, and NCH.sub.3; x is 0, 1, 2, 3 or 4,
and y is 1, 2, 3, 4 or 5, the total of x and y being greater or
equal to 1 and less than or equal to 5 (1.ltoreq.x+y.ltoreq.5);
each R.sub.2 is independently selected from halo, cyano (CN),
C.sub.1-6alkyl, C.sub.1-6alkoxy, haloalkyl, haloalkoxy, and
C.sub.3-7cycloalkyl; n is 0, 1 or 2; each X is independently
selected from a direct bond and (CR.sub.8R.sub.9).sub.p; each
R.sub.8 is independently selected from hydrogen, methyl, and
fluoro; each R.sub.9 is independently selected from hydrogen,
methyl, and fluoro; p is 1, 2, 3, 4, or 5; each R.sub.3 is
independently selected from hydrogen, cyano (CN),
C.sub.3-7cycloalkyl, optionally substituted
C.sub.5-6heterocycloalkyl, optionally substituted aryl, and
optionally substituted heteroaryl; R.sub.4 is selected from
hydrogen, methyl, and ethyl; W is selected from N, and CR.sub.10;
R.sub.10 is selected from hydrogen, halo, cyano (CN), methyl
sulfonyl (SO.sub.2CH.sub.3), C.sub.1-6alkyl, C.sub.1-6alkoxy,
haloalkyl, haloalkoxy, and C.sub.3-7cycloalkyl; provided that when
W is N and n is 1 and R.sub.2 is butyl, at least one of the
XR.sub.3 groups is not hydrogen.
2. A compound of Formula (I) as claimed in claim 1, or a salt or
solvate thereof, including a solvate of such a salt, wherein n is 0
or 1.
3. A compound of Formula (I) as claimed in claim 2, or a salt or
solvate thereof, including a solvate of such a salt, wherein n is
0.
4. A compound of Formula (I) as claimed in any of the preceding
claims, or a salt or solvate thereof, including a solvate of such a
salt, wherein at least one of the XR.sub.3 groups is not
hydrogen.
5. A compound of Formula (I) as claimed in claim 4, or a salt or
solvate thereof, including a solvate of such a salt, wherein either
one of the XR.sub.3 groups is not hydrogen and the other XR.sub.3
group is hydrogen.
6. A compound of Formula (I) as claimed in claim 1, or a salt or
solvate thereof, including a solvate of such a salt, which is a
compound of Formula (II): ##STR00571##
7. A compound of Formula (II) as claimed in claim 6, or a salt or
solvate thereof, including a solvate of such a salt, wherein n is 0
or 1.
8. A compound of Formula (II) as claimed in claim 7, or a salt or
solvate thereof, including a solvate of such a salt, wherein n is 0
and W is C-halo or C-cyano.
9. A compound of Formula (II) as claimed in any of claims 6 to 8,
or a salt or solvate thereof, including a solvate of such a salt,
wherein the XR.sub.3 group is not hydrogen.
10. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein R.sub.1 is Z.sub.q1B and q.sub.1 is
0, and each B is independently selected from halo, CN, optionally
substituted aryl, optionally substituted heteroaryl, and A.
11. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein R.sub.1 is Z.sub.q1B and q.sub.1 is
1, 2 or 3, each Z is independently selected from C.sub.1-3alkyl,
and each B is independently selected from halo, CN, optionally
substituted aryl, optionally substituted heteroaryl, and A.
12. A compound of Formula (I) or Formula (II) as claimed in claim
10 or claim 11, or a salt or solvate thereof, including a solvate
of such a salt, wherein each B is independently selected from halo,
optionally substituted C.sub.5-6heteroaryl, and
C.sub.5-6heterocycloalkyl.
13. A compound of Formula (I) or Formula (II) as claimed in claim
12, or a salt or solvate thereof, including a solvate of such a
salt, wherein each B is independently selected from bromo, chloro,
fluoro, pyridyl, pyrazolyl, methyl-pyrazolyl, oxazolyl, isoxazolyl,
dimethyl-isoxazolyl, imidazolyl, thiophenyl, pyrrolyl, piperidinyl,
pyrrolidinyl, and morpholinyl.
14. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein R.sub.1 is Z.sub.q1B and q.sub.1 is
1, 2, 3, 4, 5 or 6, each Z is independently selected from
CR.sub.5R.sub.6, O, C.dbd.O, and SO.sub.2, each R.sub.5 is
independently selected from hydrogen, methyl, and halo, each
R.sub.6 is independently selected from hydrogen, methyl, and halo,
and each B is selected from hydrogen, halo, and cyano.
15. A compound of Formula (I) or Formula (II) as claimed in claim
14, or a salt or solvate thereof, including a solvate of such a
salt, wherein each R.sub.1 is independently selected from butyl
(including tert-butyl), propyl (including isopropyl), methyl,
trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy,
carboxy-methyl, (CO)CH.sub.3, methyl sulfonyl (SO.sub.2CH.sub.3),
(CH.sub.2).sub.3OCH.sub.3, and C(CH.sub.3)(CH.sub.3)CN.
16. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein m is 0, 1 or 2.
17. A compound of Formula (I) or Formula (II) as claimed in claim
16, or a salt or solvate thereof, including a solvate of such a
salt, wherein m is 1 and R.sub.1 is para to the sulfonamide, or m
is 2 and one R.sub.1 group is meta to the sulfonamide and the other
R.sub.1 group is para to the sulfonamide.
18. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein each R.sub.2 is independently
selected from halo, cyano (CN), C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3haloalkyl, and cyclopropyl.
19. A compound of Formula (I) or Formula (II) as claimed in claim
18, or a salt or solvate thereof, including a solvate of such a
salt, wherein each R.sub.2 is independently selected from bromo,
chloro, cyano, methyl, methoxy (CH.sub.3O), propoxy (including
isopropoxy), trifluoromethyl, and cyclopropyl.
20. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein each X is independently selected
from a direct bond, CH.sub.2, CH.sub.2CH.sub.2,
C(CH.sub.3)(CH.sub.3) and C(CH.sub.3)(CH.sub.3)CH.sub.2.
21. A compound of Formula (I) or Formula (II) as claimed in claim
20, or a salt or solvate thereof, including a solvate of such a
salt, wherein X is selected from a direct bond, CH.sub.2, and
CH.sub.2CH.sub.2.
22. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein each R.sub.3 is independently
selected from hydrogen, C.sub.3-7cycloalkyl, optionally substituted
C5-6heterocycloalkyl, optionally substituted aryl, and optionally
substituted heteroaryl.
23. A compound of Formula (I) or Formula (II) as claimed in claim
22, or a salt or solvate thereof, including a solvate of such a
salt, wherein each R.sub.3 is selected from hydrogen, cyclopropyl,
optionally substituted piperidinyl, optionally substituted phenyl,
optionally substituted pyridyl, optionally substituted thiophenyl,
optionally substituted pyrazolyl, optionally substituted pyridonyl,
optionally substituted pyrimidinyl, optionally substituted
pyrazinyl, optionally substituted imidazolyl, optionally
substituted pyridazinyl, optionally substituted thiazolyl,
optionally substituted oxazolyl, optionally substituted pyrrolyl,
and optionally substituted isoquinoline.
24. A compound of Formula (I) or Formula (II) as claimed in claim
23, or a salt or solvate thereof, including a solvate of such a
salt, wherein each R.sub.3 is selected from hydrogen, cyclopropyl,
optionally substituted pyridyl, optionally substituted thiophenyl,
optionally substituted pyrazolyl, optionally substituted
pyridazinyl, optionally substituted oxazolyl, and optionally
substituted pyrrolyl.
25. A compound of Formula (I) or Formula (II) as claimed in claim
24, or a salt or solvate thereof, including a solvate of such a
salt, wherein each R.sub.3 is selected from hydrogen, cyclopropyl,
pyridyl, cyano-pyridyl, fluoro-pyridyl, methoxy-pyridyl, pyridine-N
oxide, methoxy-pyridine-N oxide, ethoxy-pyridyl, ethoxy-pyridyl
N-oxide, methyl-pyridyl and methyl-pyridyl N-oxide,
thiophenyl-CO.sub.2H, pyrazolyl, methyl-pyrazolyl,
dimethyl-pyrazolyl, pyridazinyl, oxazolyl, and methyl-pyrrolyl.
26. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein R.sub.4 is hydrogen.
27. A compound of Formula (I) or Formula (II) as claimed in any of
the preceding claims, or a salt or solvate thereof, including a
solvate of such a salt, wherein W is selected from N, CH, C-halo,
and C-cyano.
28. A compound of Formula (I) as claimed in claim 1 or a compound
of Formula (II) as claimed in claim 6, or a salt or solvate
thereof, including a solvate of such a salt, wherein m is 2, one
R.sub.1 group is halo and the other R.sub.1 group is
trifluoromethyl, n is 0, X is CH.sub.2CH.sub.2, R.sub.3 is
hydrogen, R.sub.4 is hydrogen, and W is N.
29. A compound of Formula (I) as claimed in claim 1 or a compound
of Formula (II) as claimed in claim 6, or a salt or solvate
thereof, including a solvate of such a salt, wherein R.sub.1 is
C.sub.5-6heterocycloalkyl, m is 1, n is 0, X is CH.sub.2, R.sub.3
is hydrogen, R.sub.4 is hydrogen, and W is N
30. A compound of Formula (I) as claimed in claim 1 or a compound
of Formula (II) as claimed in claim 6, or a salt or solvate
thereof, including a solvate of such a salt, wherein R.sub.1 is
optionally substituted heteroaryl, m is 1, n is 0, X is CH.sub.2,
R.sub.3 is hydrogen, R.sub.4 is hydrogen, and W is N.
31. A compound of Formula (I) as claimed in claim 1 or a compound
of Formula (II) as claimed in claim 6, or a salt or solvate
thereof, including a solvate of such a salt, wherein R.sub.1 is
butyl (including tert-butyl), m is 1, n is 0, X is a direct bond,
R.sub.3 is optionally substituted heteroaryl, R.sub.4 is hydrogen,
and W is N.
32. A compound of Formula (I) as claimed in claim 1 or a compound
of Formula (II) as claimed in claim 6, or a salt or solvate
thereof, including a solvate of such a salt, wherein R.sub.1 is
selected from tert-butyl, trifluoromethyl, trifluoromethoxy,
difluoromethoxy, and methoxy, m is 1, n is 0, X is a direct bond,
R.sub.3 is cyclopropyl, R.sub.4 is hydrogen, and W is N.
33. A compound of Formula (I) as claimed in claim 1 or a compound
of Formula (II) as claimed in claim 6, or a salt or solvate
thereof, including a solvate of such a salt, wherein R.sub.1 is
selected from halo, tert-butyl, trifluoromethyl, trifluoromethoxy,
or difluoromethoxy, m is 1, n is 0, X is selected from CH.sub.2,
CH.sub.2CH.sub.2, and C(CH.sub.3)(CH.sub.3), R.sub.3 is hydrogen,
R.sub.4 is hydrogen, and W is N.
34. A compound of Formula (II) as claimed in claim 6, or a salt or
solvate thereof, including a solvate of such a salt, wherein m is
1, R.sub.1 is butyl (including tert-butyl), n is 0, XR.sub.3 is
selected from methyl, cyclopropyl, optionally substituted pyridyl,
optionally substituted thiophenyl, optionally substituted
pyrazolyl, optionally substituted pyridazinyl, optionally
substituted oxazolyl, and optionally substituted pyrrolyl, R.sub.4
is hydrogen, and W is C-chloro or C-cyano.
35. A compound of Formula (II) as claimed in claim 6, or a salt or
solvate thereof, including a solvate of such a salt, wherein m is
1, R.sub.1 is butyl (including tert-butyl), n is 1, R.sub.2 is
chloro or cyano, XR.sub.3 is selected from methyl, cyclopropyl,
optionally substituted pyridyl, optionally substituted thiophenyl,
optionally substituted pyrazolyl, optionally substituted
pyridazinyl, optionally substituted oxazolyl, and optionally
substituted pyrrolyl, R.sub.4 is hydrogen, and W is CH.
36. A compound of Formula (I) as claimed in claim 1 or a compound
of Formula (II) as claimed in claim 6, or a salt or solvate
thereof, including a solvate of such a salt, which is any one of
Compounds 1 to 211 as listed in Table 1.
37. A compound of Formula (I) as claimed in claim 1 or a compound
of Formula (II) as claimed in claim 6, or a salt or solvate
thereof, including a solvate of such a salt, for use in
therapy.
38. A compound of Formula (I) or Formula (II) as claimed in claim
37, or a salt or solvate thereof, including a solvate of such a
salt, for use in the treatment, prevention or amelioration of a
disease or condition associated with CCR9 activation.
39. A compound of Formula (I) or Formula (II) as claimed in claim
38, or a salt or solvate thereof, including a solvate of such a
salt, for use in the treatment, prevention or amelioration of an
inflammatory disease or condition, or an immune disorder.
40. A compound of Formula (I) or Formula (II) as claimed in claim
39, or a salt or solvate thereof, including a solvate of such a
salt, for use in the treatment, prevention or amelioration of
Crohn's disease or ulcerative colitis.
41. A compound of Formula (I) or Formula (II) as claimed in claim
40, or a salt or solvate thereof, including a solvate of such a
salt, for use in the treatment, prevention or amelioration of
Crohn's disease.
42. Use of a compound of Formula (I) as claimed in claim 1 or a
compound of Formula (II) as claimed in claim 6, or a salt or
solvate thereof, including a solvate of such a salt, in the
treatment, prevention or amelioration of a disease or condition
associated with CCR9 activation.
43. A method of treating, preventing or ameliorating a disease or
condition associated with CCR9 activation in a subject, which
comprises administering an effective amount of a compound of
Formula (I) as claimed in claim 1 or a compound of Formula (II) as
claimed in claim 6, or a salt or solvate thereof, including a
solvate of such a salt, to the subject.
44. A composition comprising a compound of Formula (I) or Formula
(II) as claimed in any of claims 1 to 41, or a salt or solvate
thereof, including a solvate of such a salt, together with an
acceptable carrier.
45. Use of a composition as claimed in claim 44 in the treatment,
prevention or amelioration of a disease or condition associated
with CCR9 activation.
46. A method of treating, preventing or ameliorating a disease or
condition associated with CCR9 activation in a subject, which
comprises administering an effective amount of a composition as
claimed in claim 44 to the subject.
47. A process for the preparation of a compound of Formula (I) as
claimed in claim 1, wherein the process is selected from the
processes shown in Scheme 1, Scheme 2, Scheme 3, and Scheme 4.
Description
[0001] The present invention relates to compounds useful as CCR9
modulators, to compositions containing them, to methods of making
them, and to methods of using them. In particular, the present
invention relates to compounds capable of modulating the function
of the CCR9 receptor by acting as partial agonists, antagonists or
inverse agonists. Such compounds may be useful to treat, prevent or
ameliorate a disease or condition associated with CCR9 activation,
including inflammatory and immune disorder diseases or conditions
such as inflammatory bowel diseases (IBD).
BACKGROUND OF THE INVENTION
[0002] Chemokines are a family of structurally related small
proteins released from a variety of different cells within the body
(reviewed in Vinader et al, 2012, Future Med Chem, 4(7): 845-52).
The name derives from their primary ability to induce chemotaxis
and thereby attract multiple cells of the immune system to sites of
inflammation or as a part of normal immune function homeostasis.
Examples of the types of cells attracted by chemokines include
monocytes, T and B lymphocytes, dendritic cells, natural killer
cells, eosinophils, basophils and neutrophils. Chemokines, in
addition to their primary role in inducing chemotaxis, are also
able to cause activation of leukocytes at the site of
inflammation--for example, but not limited to, causing
degranulation of granulocytes, generation of super-oxide anions
(oxidative burst) and up-regulation of integrins to cause
extravasation. Chemokines initiate their biological activity
through binding to and activation of cell surface
receptors--chemokine receptors. Chemokine receptors belong to the
G-coupled protein receptor (GPCR), 7-trans-membrane (7-TM)
superfamily--comprising an extracellular N-terminus with 7 helical
trans-membrane domains and an intracellular C-terminus.
Traditionally, chemokines are considered to bind to their receptors
in the 7-TM region--this binding leading to activation of the
receptor and resulting in G-protein activation (and subsequent
secondary messenger transmission) by the intracellular portion of
the receptor.
[0003] CCR9 is a chemokine receptor shown to be expressed on
circulating T lymphocytes (Zabel et al, 1999, J Exp Med,
190:1241-56) and, in contrast to the majority of human chemokine
receptors, CCR9 currently has only a single ligand identified:
CCL25, otherwise known as thymus-expressed chemokine (TECK)
(Zabalos et al, 1999, J Immunol, 162: 5671-5). As CCL25 expression
is limited to intestinal epithelium and the thymus (Kunkel et al,
2000, J Exp Med, 192(5): 761-8), this interaction has been
demonstrated to be the key chemokine receptor involved in targeting
of T lymphocytes to the intestine (Papadakis et al, 2000, J
Immunol, 165(9): 5069-76). The infiltration of T lymphocytes into
tissues has been implicated in a broad range of diseases,
including, but not limited to, such diseases as asthma, rheumatoid
arthritis and inflammatory bowel disease (IBD). Specific to IBD, it
has been observed that CCR9+CD4 and CD8 T lymphocytes are increased
in disease alongside an increased expression of CCL25 that
correlates with disease severity (Papadakis et al, 2001,
Gastroenterology, 121(2): 246-54). Indeed, disruption of the
CCR9/CCL25 interaction by antibody and small molecule antagonists
of CCR9 has been demonstrated to be effective in preventing the
inflammation observed in small animal models of IBD (Rivera-Nieves
et al, 2006, Gastroenterology, 131(5): 1518-29 and Walters et al,
2010, J Pharmacol Exp Ther, 335(1):61-9). In addition to the IBD
specific role for CCR9, recent data also implicates the CCR9/CCL25
axis in liver inflammation and fibrosis where increased expression
of CCL25 has been observed in the inflamed liver of primary
sclerosing cholangitis patients along with a concomitant increase
in the numbers of CCR9+ T lymphocytes (Eksteen et al, 2004, J Exp
Med, 200(11):1511-7). CCR9+macrophages have also been observed in
in vivo models of liver disease and their function proven with
CCL25 neutralising antibodies and CCR9-knockout mice exhibiting a
reduction in CCR9+ macrophage number, hepatitis and liver fibrosis
(Nakamoto et al, 2012, Gastroenterol, 142:366-76 and Chu et al,
2012, 63.sup.rd Annual Meeting of the American Association for the
Study of Liver Diseases, abstract 1209). Therefore, modulation of
the function of CCR9 represents an attractive target for the
treatment of inflammatory, immune disorder and other conditions and
diseases associated with CCR9 activation, including IBD and liver
disease.
[0004] In addition to inflammatory conditions, there is increasing
evidence for the role of CCR9 in cancer. Certain types of cancer
are caused by T lymphocytes expressing CCR9. For example, in
thymoma and thymic carcinoma (where cancer cells are found in the
thymus), the developing T lymphocytes (thymocytes) are known to
express high levels of CCR9 and CCL25 is highly expressed in the
thymus itself. In the thymus, there is evidence that the CCR9/CCL25
interaction is important for thymocyte maturation (Svensson et al,
2008, J Leukoc Biol, 83(1): 156-64). In another example, T
lymphocytes from acute lymphocytic leukaemia (ALL) patients express
high levels of CCR9 (Qiuping et al, 2003, Cancer Res, 63(19):
6469-77). While the role for chemokine receptors is not clear in
the pathogenesis of cancer, recent work has indicated that
chemokine receptors, including CCR9, are important in metastasis of
tumours--with a potential therapeutic role suggested for chemokine
receptor antagonists (Fusi et al, 2012, J Transl Med, 10:52).
Therefore, blocking the CCR9/CCL25 interaction may help to prevent
or treat cancer expansion and/or metastasis.
[0005] Inflammatory bowel diseases (IBD) are chronic inflammatory
disorders of the gastrointestinal tract in which tissue damage and
inflammation lead to long-term, often irreversible impairment of
the structure and function of the gastrointestinal tract (Bouma and
Strober, 2003, Nat Rev Immunol, 3(7):521-533). Inflammatory bowel
diseases may include collagenous colitis, lymphocytic colitis,
ischaemic colitis, diversion colitis, Behcet's disease (also known
as Behcet's syndrome), indeterminate colitis, ileitis and
enteritis, but Crohn's disease and ulcerative colitis are the most
common forms of IBD. Crohn's disease and ulcerative colitis both
involve chronic inflammation and ulceration in the intestines, the
result of an abnormal immune response. Chronic and abnormal
activation of the immune system leads to tissue destruction in both
diseases, although ulcerative colitis is generally limited to the
rectum and colon, whereas Crohn's disease (also known as regional
ileitis) extends deeper in the intestinal wall and can involve the
entire digestive tract, from the mouth to the anus.
[0006] Up to one million Americans have inflammatory bowel disease,
according to an estimate by the Crohn's and Colitis Foundation of
America. The incidence of IBD is highest in Western countries. In
North America and Europe, both ulcerative colitis and Crohn's
disease have an estimated prevalence of 10-20 cases per 100,000
populations (Bouma and Strober, 2003).
[0007] The primary goal when treating a patient with IBD is to
control active disease until a state of remission is obtained; the
secondary goal is to maintain this state of remission (Kamm, 2004,
Aliment Pharmacol Ther, 20(4):102). Most treatments for IBD are
either medical or surgical (typically only used after all medical
options have failed). Some of the more common drugs used to treat
IBD include 5-aminosalicylic acid (5-ASA) compounds (such as
sulfasalazine, mesalamine, and olsazine), immunosuppressants (such
as azathioprine, 6-mercaptopurine (6-MP), cyclosporine A and
methotrexate), corticosteroids (such as prednisone,
methylprednisolone and budesonide), infliximab (an anti-TNF.alpha.
antibody) and other biologics (such as adilumumab, certolizumab and
natalizumab). None of the currently available drugs provides a
cure, although they can help to control disease by suppressing
destructive immune processes, promoting healing of intestinal
tissues and relieving symptoms (diarrhoea, abdominal pain and
fever).
[0008] There is a need to develop alternative drugs for the
treatment of IBD, with increased efficacy and/or improved safety
profile (such as reduced side effects) and/or improved
pharmacokinetic properties. Treatment of IBD includes control or
amelioration of the active disease, maintenance of remission and
prevention of recurrence.
[0009] Various new drugs have been in development, including the
aryl sulfonamide compound
N-{4-chloro-2-[(1-oxidopyridin-4-yl)carbonyl]phenyl}-4-(1,1-dimethylethyl-
) benzenesulfonamide, also known as Vercirnon or GSK1605786 (CAS
Registry number 698394-73-9), and Vercirnon sodium. Vercirnon was
taken into Phase III clinical development for the treatment of
patients with moderate-to-severe Crohn's disease. Vercirnon is the
compound claimed in U.S. Pat. No. 6,939,885 (Chemocentryx) and is
described as an antagonist of the CCR9 receptor. Various other aryl
sulfonamide compounds have also been disclosed as CCR9 antagonists
that may be useful for the treatment of CCR9-mediated diseases such
as inflammatory and immune disorder conditions and diseases; for
example, see the following Chemocentryx patent applications,
WO2004/046092 which includes Vercirnon, WO2004/085384,
WO2005/112916, WO2005/112925, WO2005/113513, WO2008/008374,
WO2008/008375, WO2008/008431, WO2008/010934, WO2009/038847; also
WO2003/099773 (Millennium Pharmaceuticals), WO2007/071441
(Novartis) and US2010/0029753 (Pfizer).
[0010] Thus a number of CCR9-modulating compounds are known and
some are being developed for medical uses (see, for example, the
review of CCR9 and IBD by Koenecke and Forster, 2009, Expert Opin
Ther Targets, 13 (3):297-306, or the review of CCR antagonists by
Proudfoot, 2010, Expert Opin Investig Drugs, 19(3): 345-55).
Different classes of compounds may have different degrees of
potency and selectivity for modulating CCR9. There is a need to
develop alternative CCR9 modulators with improved potency and/or
beneficial activity profiles and/or beneficial selectivity profiles
and/or increased efficacy and/or improved safety profiles (such as
reduced side effects) and/or improved pharmacokinetic
properties.
[0011] Other classes of compounds with different biological targets
have been suggested for different uses. For example,
pyrazolo[1,5-a]pyrimidine derivatives said to be useful as
analgesic compounds are disclosed in European patent publication
number 0714898 (Otsuka Pharmaceutical Factory, Inc); for example,
see compounds 127 and 128 in Table 4 of EP0714898.
[0012] We now provide a new class of compounds that are useful as
CCR9 modulators, and in particular as partial agonists, antagonists
or inverse agonists of CCR9. The compounds of the invention may
have improved potency and/or beneficial activity profiles and/or
beneficial selectivity profiles and/or increased efficacy and/or
improved safety profiles (such as reduced side effects) and/or
improved pharmacokinetic properties. Some of the preferred
compounds may show selectivity for CCR9 over other receptors, such
as other chemokine receptors.
[0013] Such compounds may be useful to treat, prevent or ameliorate
a disease or condition associated with CCR9 activation, including
inflammatory and immune disorder diseases or conditions such as
inflammatory bowel diseases (IBD).
SUMMARY OF THE INVENTION
[0014] The present invention provides a compound of Formula (I) or
a salt or solvate thereof, including a solvate of such a salt:
##STR00002##
[0015] in which:
[0016] each R.sub.1 is Z.sub.q1B;
[0017] m is 0, 1, 2 or 3;
[0018] q.sub.1 is 0, 1, 2, 3, 4, 5 or 6;
[0019] each Z is independently selected from CR.sub.5R.sub.6, O,
C.dbd.O, SO.sub.2, and NR.sub.7;
[0020] each R.sub.5 is independently selected from hydrogen,
methyl, ethyl, and halo;
[0021] each R.sub.6 is independently selected from hydrogen,
methyl, ethyl, and halo;
[0022] each R.sub.7 is independently selected from hydrogen,
methyl, and ethyl;
[0023] each B is independently selected from hydrogen, halo, cyano
(CN), optionally substituted aryl,
[0024] optionally substituted heteroaryl, optionally substituted
cycloalkyl, and A;
[0025] A is
##STR00003##
[0026] Q is selected from CH.sub.2, O, NH, and NCH.sub.3;
[0027] x is 0, 1, 2, 3 or 4, and y is 1, 2, 3, 4 or 5, the total of
x and y being greater or equal to 1 and less than or equal to 5
(1.ltoreq.x+y.ltoreq.5);
[0028] each R.sub.2 is independently selected from halo, cyano
(CN), C.sub.1-6 alkyl, C.sub.1-6alkoxy, haloalkyl, haloalkoxy, and
C.sub.3-7 cycloalkyl;
[0029] n is 0, 1 or 2;
[0030] each X is independently selected from a direct bond and
(CR.sub.8R.sub.9).sub.p;
[0031] each R.sub.8 is independently selected from hydrogen,
methyl, and fluoro;
[0032] each R.sub.9 is independently selected from hydrogen,
methyl, and fluoro;
[0033] p is 1, 2, 3, 4, or 5;
[0034] each R.sub.3 is independently selected from hydrogen, cyano
(CN), C.sub.3-7 cycloalkyl, optionally substituted C.sub.5-6
heterocycloalkyl, optionally substituted aryl, and optionally
substituted heteroaryl;
[0035] R.sub.4 is selected from hydrogen, methyl, and ethyl;
[0036] W is selected from N, and CRio;
[0037] R.sub.10 is selected from hydrogen, halo, cyano (CN), methyl
sulfonyl (SO.sub.2CH.sub.3), C.sub.1-6 alkyl, C.sub.1-6alkoxy,
haloalkyl, haloalkoxy, and C.sub.3-7 cycloalkyl;
[0038] provided that when W is N and n is 1 and R.sub.2 is butyl,
at least one of the XR.sub.3 groups is not hydrogen.
[0039] It will be appreciated that the compounds of the invention
may contain one or more asymmetrically substituted carbon atoms.
The presence of one or more of these asymmetric centres (chiral
centres) in a compound of Formula (I) can give rise to
stereoisomers, and in each case the invention is to be understood
to extend to all such stereoisomers, including enantiomers and
diastereomers, and mixtures thereof (including racemic mixtures
thereof).
[0040] Where tautomers exist in the compounds of Formula (I), we
disclose all individual tautomeric forms and combinations of these
as individual specific embodiments of the invention.
[0041] In addition, the invention is to be understood to extend to
all isomers which are compounds with one or more isotopic
substitutions. For example, H may be in any isotopic form,
including .sup.1H, .sup.2H(D), and .sup.3H(T); C may be in any
isotopic form, including .sup.12C, .sup.13C, and .sup.14C; O may be
in any isotopic form, including .sup.16O and .sup.18O; and the
like.
[0042] It will be appreciated that the particular groups or
substituents, the number of groups or substituents, and the
position of substitution in compounds of Formula (I) are selected
so as to avoid sterically undesirable combinations.
[0043] When present, each of the R.sub.1 and R.sub.2 groups may be
attached at any suitable position. An R.sub.1 group may be para,
meta or ortho to the sulfonamide, especially para. For example,
when m is 1, then R.sub.1 is preferably meta or para to the
sulfonamide, and most preferably para to the sulfonamide; and when
m is 2, then most preferably one R.sub.1 group is meta to the
sulfonamide and the other R.sub.1 group is para to the sulfonamide.
An R.sub.2 group may be ortho or meta to the sulfonamide,
especially ortho. For example, when W is N or CH, and n is 1, then
R.sub.2 is most preferably ortho to the sulfonamide.
[0044] Certain compounds of the invention may act as prodrugs, or
may be converted into prodrugs by known methods, and in each case
the invention is to be understood to extend to all such
prodrugs.
[0045] Except where otherwise stated, throughout this specification
and claims, any of the following groups present in a compound of
the invention or in an intermediate used for the preparation of a
compound of the invention, is as defined below: [0046] an alkyl
group is any branched or unbranched (straight chain) hydrocarbon,
and may for example contain from 1 to 7 carbon atoms, especially
from 1 to 6 carbon atoms; [0047] a cycloalkyl group is any
monocyclic saturated hydrocarbon ring structure, and may for
example contain from 3 to 7 carbon atoms, especially 3, 4, 5 or 6
carbon atoms; [0048] a heteroalkyl group is any alkyl group wherein
any one or more carbon atoms is replaced by a heteroatom
independently selected from N, O, S; [0049] a heterocycloalkyl
group is any cycloalkyl group wherein any one or more carbon atoms
is replaced by a heteroatom independently selected from N, O, S;
[0050] an aryl group is any polyunsaturated, aromatic hydrocarbon
group having a single ring or multiple rings which are fused
together or linked covalently; aryl groups with up to 10 carbon
atoms are preferred, particularly a monocyclic aryl group having 6
carbon atoms; examples of aryl groups include phenyl, biphenyl and
naphthalene; [0051] a heteroaryl group is any aryl group wherein
any one or more carbon atoms is replaced by a heteroatom
independently selected from N, O, S; heteroaryl groups with 5 to 10
ring atoms are preferred, particularly a monocyclic heteroaryl
group having 5 or 6 ring atoms; examples of heteroaryl groups
include pyridyl, pyrazolyl, pyridazinyl, pyrrolyl, oxazolyl,
quinolinyl and isoquinolinyl; [0052] a halo group is any halogen
atom, and may for example be fluorine (F), chlorine (Cl) or bromine
(Br), and especially fluorine or chlorine; [0053] a haloalkyl group
is any alkyl group substituted with one or more halogen atoms,
particularly 1, 2 or 3 halogen atoms, especially fluorine or
chlorine;
[0054] an alkoxy group is any Oalkyl group, especially OC.sub.1-6
alkyl; [0055] a haloalkoxy group is any Ohaloalkyl group,
especially OC.sub.1-6 haloalkyl.
[0056] Except where otherwise stated, throughout this specification
and claims, the phrase "optionally substituted" means unsubstituted
or substituted by up to three groups ("optional substituents")
independently selected from OH, .dbd.O or O.sup.-, NO.sub.2,
CF.sub.3, CN, halo (such as Cl or F or Br), CHO, CO.sub.2H,
C.sub.1-4alkyl (such as methyl), C.sub.3-7cycloalkyl,
C.sub.1-4alkoxy (such as --O-methyl, --O-ethyl), COC.sub.1-4alkyl
(such as --(CO)-methyl), COC.sub.1-4alkoxy (such as
--(CO)--O-methyl), and C.sub.1-4haloalkoxy.
[0057] Except where otherwise stated, throughout this specification
and claims, the term "prodrug" means a compound which, upon
administration to the recipient, has very low activity or is
inactive in its administered state but is capable of providing
(directly or indirectly) an active compound or an active metabolite
thereof. A prodrug is converted within the body into its active
form which has medical effects.
DETAILED DESCRIPTION OF THE INVENTION
[0058] The compounds as defined above are useful as CCR9
modulators, and in particular as partial agonists, antagonists or
inverse agonists of CCR9. Such compounds may be useful to treat,
prevent or ameliorate a disease or condition associated with CCR9
activation, including inflammatory and immune disorder diseases or
conditions. Such diseases or conditions include inflammatory bowel
diseases (IBD). In particular, the compounds as defined above may
be useful to treat, prevent or ameliorate Crohn's disease and/or
ulcerative colitis, and most particularly Crohn's disease.
[0059] The compounds as defined above are novel. Accordingly, the
present invention provides a compound of Formula (I) as defined
above or a salt or solvate thereof, including a solvate of such a
salt, per se. In particular, the present invention provides a
compound of Formula (I) as defined above or a pharmaceutically
acceptable salt or solvate thereof, including a solvate of such a
salt, per se. Most particularly, the present invention provides a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof, per se.
[0060] In order to use a compound of Formula (I) or a salt or
solvate thereof for therapy, it is normally formulated in
accordance with standard practice as a composition.
[0061] Thus the invention also provides a composition comprising a
compound of Formula (I) or a salt or solvate thereof, including a
solvate of such a salt, together with an acceptable carrier. In
particular, the invention provides a pharmaceutical composition
comprising a compound of Formula (I) or a salt or solvate thereof,
including a solvate of such a salt, together with a
pharmaceutically acceptable carrier.
[0062] The invention further provides a compound according to the
invention for use in therapy, specifically, for use in the
treatment, prevention or amelioration of a disease or condition
associated with CCR9 activation, including inflammatory and immune
disorder diseases or conditions. Such diseases or conditions
include: (1) Inflammatory bowel diseases (IBD) such as Crohn's
disease, ulcerative colitis, collagenous colitis, lymphocytic
colitis, ischaemic colitis, diversion colitis, Behget's disease,
indeterminate colitis, ileitis and enteritis; (2) allergic diseases
such as systemic anaphylaxis or hypersensitivity responses, drug
allergies, insect sting allergies and food allergies; (3)
immune-mediated food allergies such as Coeliac (Celiac) disease;
(4) autoimmune diseases, such as rheumatoid arthritis,
fibromyalagia, scleroderma, ankylosing spondylitis, juvenile RA,
Still's disease, polyarticular juvenile RA, pauclarticular juvenile
RA, polymyalgia rheumatica, psoriatic arthritis, osteoarthritis,
polyarticular arthritis, multiple scerlosis, systemic lupus
erythematosus, type I diabetes, type II diabetes,
glomerulonephritis, and the like; (5) psoriasis and inflammatory
dermatoses such as dermatitis, eczema, atopic dermatitis, allergic
contact dermatitis, urticaria and pruritus; (6) asthma and
respiratory allergic diseases such as allergic asthma, allergic
rhinitis, hypersensitivity lung diseases and the like; (7)
vaginitis; (8) vasculitis; (9) spondyloarthropathies; (10)
scleroderma; (11) graft rejection (including allograft rejection);
(12) graft-v-host disease (including both acute and chronic); (13)
other diseases in which undesired inflammatory responses are to be
inhibited, such as atherosclerosis, myositis, neurodegenerative
diseases (such as Alzheimer's disease), encephalitis, meningitis,
liver diseases (such as liver inflammation, liver fibrosis,
hepatitis, NASH), nephritis, sepsis, sarcoidosis, allergic
conjunctivitis, otitis, chronic obstructive pulmonary disease,
sinusitis, Behcet's disease and gout; (14) cancers, such as thymoma
and thymic carcinoma, and acute lymphocytic leukemia (ALL, also
known as acute lymphoblastic leukemia).
[0063] In particular, the invention provides a compound according
to the invention for use to treat, prevent or ameliorate Crohn's
disease and/or ulcerative colitis, and most particularly Crohn's
disease.
[0064] The invention further provides the use of a compound of the
invention for the treatment, prevention or amelioration of diseases
or conditions as mentioned above; the use of a compound of the
invention for the manufacture of a medicament for the treatment,
prevention or amelioration of diseases or conditions as mentioned
above; and a method of treating, preventing or ameliorating a
disease or condition as mentioned above in a subject, which
comprises administering an effective amount of a compound or a
composition according to the invention to said subject. The subject
to be treated according to the present invention is typically a
mammal. The mammal is generally a human but may for example be a
commercially reared animal or a companion animal.
[0065] A compound of Formula (I) may also be used as an
intermediate in a method to synthesise another chemical compound,
including but not limited to another compound of Formula (I); as a
reagent in an analytical method; as a research tool--for example,
as a comparator compound in an assay, or during compound screening
to assist in identifying and/or profiling a compound with similar
or differing activity in the test conditions applied, or as a
control in cell based, in vitro and/or in vivo test assays.
[0066] In preferred compounds of Formula (I), n is 0 or 1, and in
particularly preferred compounds of Formula (I), n is 0 (so there
is no R.sub.2 group present).
[0067] In preferred compounds of Formula (I), at least one of the
XR.sub.3 groups is not hydrogen; most especially, either one of the
XR.sub.3 groups is not hydrogen and the other XR.sub.3 group is
hydrogen (ie X is a direct bond and R.sub.3 is H). Particularly
preferred compounds of Formula (I) are compounds of Formula
(II):
##STR00004##
[0068] wherein the definitions of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, X, m and n are as given above for Formula (I).
[0069] In preferred compounds of Formula (II), n is 0 or 1, and in
particularly preferred compounds of Formula (II), n is 0 (so there
is no R.sub.2 group present). In preferred compounds of Formula
(II), the XR.sub.3 group is not hydrogen. In particularly preferred
compounds of Formula (II), n is 0 and the XR.sub.3 group is not
hydrogen, or n is 0 and W is C-halo (particularly C-chloro) or
C-cyano.
[0070] In most particularly preferred compounds of Formula (II), n
is 0, the XR.sub.3 group is not hydrogen, and W is C-halo
(particularly C-chloro) or C-cyano.
[0071] Preferred compounds of Formula (I) include those wherein any
one or more of the following apply; particularly preferred
compounds are compounds of Formula (II) wherein any one or more of
the following apply: [0072] R.sub.1 is Z.sub.q1B and q.sub.1 is 0,
each B is independently selected from halo, CN, optionally
substituted aryl, optionally substituted heteroaryl, and A;
especially each B is independently selected from halo, optionally
substituted C.sub.5-6heteroaryl (particularly unsubstituted
C.sub.5-6heteroaryl), and C.sub.5-6heterocycloalkyl (where B is A,
and the total of x and y is 3 or 4, and Q is CH.sub.2 or O); more
especially each B is independently selected from bromo, chloro,
fluoro, pyridyl, pyrazolyl, methyl-pyrazolyl, oxazolyl, isoxazolyl,
dimethyl-isoxazolyl, imidazolyl, thiophenyl, pyrrolyl, piperidinyl,
pyrrolidinyl, and morpholinyl; most especially each B is
independently selected from bromo, chloro, fluoro, and oxazolyl;
particularly B is oxazolyl; and/or [0073] R.sub.1 is Z.sub.q1B and
q.sub.1 is 1, 2 or 3, each Z is independently selected from
C.sub.1-3alkyl, each B is independently selected from halo, CN,
optionally substituted aryl, optionally substituted heteroaryl, and
A; especially each B is independently selected from halo,
optionally substituted C.sub.5-6heteroaryl (particularly
unsubstituted C.sub.5-6heteroaryl), and C.sub.5-6heterocycloalkyl
(where B is A, and the total of x and y is 3 or 4, and Q is
CH.sub.2 or O); more especially each B is independently selected
from bromo, chloro, fluoro, pyridyl, pyrazolyl, methyl-pyrazolyl,
oxazolyl, isoxazolyl, dimethyl-isoxazolyl, imidazolyl, thiophenyl,
pyrrolyl, piperidinyl, pyrrolidinyl, and morpholinyl; most
especially each B is independently selected from bromo, chloro,
fluoro, and oxazolyl; particularly B is oxazolyl; and/or [0074]
R.sub.1 is Z.sub.q1B and q.sub.1 is 1, 2, 3, 4, 5 or 6,
particularly q.sub.1 is 1 or 2, each Z is independently selected
from CR.sub.5R.sub.6, O, C.dbd.O, and SO.sub.2, each R.sub.5 is
independently selected from hydrogen, methyl, and halo
(particularly fluoro), each R.sub.6 is independently selected from
hydrogen, methyl, and halo (particularly fluoro), B is selected
from hydrogen, halo (particularly fluoro), and cyano; most
especially each R.sub.1 is independently selected from butyl
(particularly tert-butyl), propyl (particularly isopropyl), methyl,
trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy,
carboxy-methyl (CO)CH.sub.3, methyl sulfonyl (SO.sub.2CH.sub.3),
(CH.sub.2).sub.3OCH.sub.3, and C(CH.sub.3)(CH.sub.3)CN;
particularly each R.sub.1 is independently selected from butyl
(particularly tert-butyl), propyl (particularly isopropyl),
trifluoromethyl, trifluoromethoxy, and C(CH.sub.3)(CH.sub.3)CN;
most particularly each R.sub.1 is independently selected from butyl
(particularly tert-butyl), and/or
[0075] m is 0, 1 or 2; especially m is 1 or 2; most especially m is
1; when m is 1, then R.sub.1 is preferably meta or para to the
sulfonamide, and most preferably para to the sulfonamide; and when
m is 2, then most preferably one R.sub.1 group is meta to the
sulfonamide and the other R.sub.1 group is para to the sulfonamide;
for example when m is 1, R.sub.1 may be meta or para to the
sulfonamide (especially para) and may be tert-butyl, isopropyl,
methyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, or
methoxy (especially R.sub.1 may be tert-butyl or trifluoromethyl);
for example when m is 2, one R.sub.1 group is meta to the
sulfonamide and the other R.sub.1 group is para to the sulfonamide,
and the two R.sub.1 groups may be trifluoromethyl and chloro or the
two R.sub.1 groups may be trifluoromethyl and fluoro; and/or
[0076] each R.sub.2 is independently selected from halo, cyano
(CN), C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3haloalkyl, and
cyclopropyl; especially each R.sub.2 is independently selected from
bromo, chloro, cyano, methyl, methoxy (CH.sub.3O), propoxy
particularly isopropoxy (Oisopropyl), trifluoromethyl, and
cyclopropyl; especially R.sub.2 is chloro, bromo or cyano; most
especially R.sub.2 is chloro or cyano; and/or [0077] n is 0 or 1;
especially n is 0 when W is N or when W is C-halo or C-cyano;
especially n is 1 when W is CH; when n is 1, the R.sub.2 group may
be ortho or meta to the sulfonamide, preferably ortho; for example,
when n is 1 and W is N or CH, then R.sub.2 is most preferably ortho
to the sulfonamide; and/or [0078] each X is independently selected
from a direct bond, CH.sub.2, CH.sub.2CH.sub.2,
C(CH.sub.3)(CH.sub.3), and C(CH.sub.3)(CH.sub.3)CH.sub.2;
especially X is selected from a direct bond, CH.sub.2, and
CH.sub.2CH.sub.2; most especially X is a direct bond or CH.sub.2;
and/or [0079] p is 1, 2, or 3 (particularly 1); and/or [0080] each
R.sub.3 is independently selected from hydrogen,
C.sub.3-7cycloalkyl, optionally substituted
C.sub.5-6heterocycloalkyl, optionally substituted aryl, and
optionally substituted heteroaryl; especially each R.sub.3 is
selected from hydrogen, cyclopropyl, optionally substituted
piperidinyl, optionally substituted phenyl, optionally substituted
pyridyl, optionally substituted thiophenyl, optionally substituted
pyrazolyl, optionally substituted pyridonyl, optionally substituted
pyrimidinyl, optionally substituted imidazolyl, optionally
substituted pyridazinyl, optionally substituted pyrazinyl,
optionally substituted thiazolyl, optionally substituted oxazolyl,
optionally substituted pyrrolyl, and optionally substituted
isoquinoline, including piperidinyl, phenyl, chloro-phenyl,
methyl-phenyl, cyano-phenyl, pyridyl, cyano-pyridyl,
chloro-pyridyl, fluoro-pyridyl, methoxy-pyridyl, pyridyl-N oxide,
methoxy-pyridyl-N oxide, ethoxy-pyridyl, ethoxy-pyridyl N-oxide,
methyl-pyridyl and methyl-pyridyl N-oxide, thiophenyl,
thiophenyl-CO.sub.2H, thiophenyl-CO.sub.2CH.sub.3, pyrazolyl,
methyl-pyrazolyl, dimethyl-pyrazolyl, pyrimidinyl, pyrazinyl,
imidazolyl, methyl-imidazolyl, pyridazinyl, thiazolyl, oxazolyl,
pyrrolyl, methyl-pyrrolyl, methyl-pyridonyl and isoquinoline;
preferred optional substituents are selected from halo
(particularly chloro or fluoro), cyano (CN), methyl, ethyl,
isopropyl, methoxy (CH.sub.3O), acetyl (CH.sub.3CO), CO.sub.2H,
CO.sub.2CH.sub.3, OH, and O--; more especially each R.sub.3 is
selected from hydrogen, cyclopropyl, optionally substituted
pyridyl, optionally substituted thiophenyl, optionally substituted
pyrazolyl, optionally substituted pyridazinyl, optionally
substituted oxazolyl, and optionally substituted pyrrolyl,
including pyridyl, cyano-pyridyl, fluoro-pyridyl, methoxy-pyridyl,
pyridyl-N oxide, methoxy-pyridyl-N oxide, ethoxy-pyridyl,
ethoxy-pyridyl N-oxide, methyl-pyridyl and methyl-pyridyl N-oxide,
thiophenyl-CO.sub.2H, pyrazolyl, methyl-pyrazolyl,
dimethyl-pyrazolyl, pyridazinyl, oxazolyl, and methyl-pyrrolyl;
most preferably each R.sub.3 is selected from hydrogen, optionally
substituted pyridyl, optionally substituted thiophenyl, optionally
substituted pyrazolyl, and optionally substituted pyrrolyl,
including pyridyl, fluoro-pyridyl, methoxy-pyridyl, pyridyl-N
oxide, methoxy-pyridyl-N oxide, methyl-pyridyl, methyl-pyridyl
N-oxide, thiophenyl-CO.sub.2H, pyrazolyl, methyl-pyrazolyl, and
methyl-pyrrolyl; and/or [0081] at least one of the XR.sub.3 groups
is not hydrogen; most especially, one of the XR.sub.3 groups is not
hydrogen and the other XR.sub.3 group (if present) is hydrogen;
and/or [0082] R.sub.4 is hydrogen; and/or [0083] W is selected from
N, CH, C-halo, and C-cyano; especially W is selected from C-halo
(particularly C-chloro) and C-cyano; most particularly W is
C-cyano.
[0084] In preferred compounds of the invention, optionally
substituted groups are those that are unsubstituted or substituted
by one or two groups independently selected from OH, .dbd.O or
O.sup.-, NO.sub.2, CF.sub.3, CN, halo (such as Cl or F or Br), CHO,
CO.sub.2H, C.sub.1-4alkyl (such as methyl, ethyl, isopropyl),
C.sub.3-7cycloalkyl, C.sub.1-4alkoxy (such as --O-methyl,
--O-ethyl), COC.sub.1-4alkyl (such as --(CO)-methyl),
COC.sub.1-4alkoxy (such as --(CO)--O-methyl), and
C.sub.1-4haloalkoxy. Preferred substituents (particularly for
R.sub.3) are selected from O.sup.-, CN, CO.sub.2H, methyl, methoxy
(--O-- methyl), ethyl, ethoxy (--O-ethyl), and CO.sub.2methyl. When
R.sub.3 is an optionally substituted aryl, each substituent may be
ortho, meta or para to the point of attachment to X. When R.sub.3
is an optionally substituted heteroaryl, each substituent may be
ortho, meta or para to the point of attachment to X, or may be
attached to a heteroatom.
[0085] For compounds of Formula (I), examples of preferred XR.sub.3
groups include those shown below plus XR.sub.3 groups wherein the
aryl or heteroaryl groups shown below are further optionally
substituted (preferably, in a compound of Formula (I), one XR.sub.3
group is selected from such preferred XR.sub.3 groups, and one
XR.sub.3 group is H; most preferably, in a compound of Formula
(II), the XR.sub.3 group is selected from such preferred XR.sub.3
groups):
##STR00005##
[0086] In certain preferred compounds of Formula (II), X is
selected from a direct bond, CH.sub.2, CH.sub.2CH.sub.2,
C(CH.sub.3)(CH.sub.3) and C(CH.sub.3)(CH.sub.3)CH.sub.2, and
R.sub.3 is hydrogen, so that XR.sub.3 is selected from H, methyl,
ethyl, isopropyl, and tert-butyl. In particular, XR.sub.3 is
selected from methyl and ethyl.
[0087] In other preferred compounds of Formula (II), X is a direct
bond and R.sub.3 is selected from cyano (CN), C.sub.3-7cycloalkyl,
optionally substituted C.sub.5-6heterocycloalkyl, optionally
substituted aryl, and optionally substituted heteroaryl.
[0088] For compounds of Formula (I), when R.sub.1 is A (ie q.sub.1
is 0 and B is A), R.sub.1 is a C.sub.3-7heterocycloalkyl containing
one heteroatom (N) or two heteroatoms (N plus O or N, where the
second N may be substituted with methyl). For example, A may be
pyrrolidinyl, piperidinyl, or morpholinyl. The group A is attached
through any of its carbon or nitrogen atoms, for example as
follows:
##STR00006##
[0089] Particular compounds of Formula (I) and Formula (II) include
those wherein: [0090] m is 2; and [0091] one R.sub.1 group is halo
(particularly bromo, chloro or fluoro, most particularly chloro,),
and the other R.sub.1 group is trifluoromethyl; and [0092] one
R.sub.1 group is meta to the sulfonamide and the other R.sub.1
group is para to the sulfonamide; and [0093] n is 0 (so there is no
R.sub.2 group present); and [0094] X is CH.sub.2CH.sub.2; and
[0095] R.sub.3 is hydrogen; and [0096] R.sub.4 is hydrogen; and
[0097] W is N. [0098] An example of such a compound is shown
below:
##STR00007##
[0099] Further particular compounds of Formula (I) and Formula (II)
include those wherein: [0100] R.sub.1 is C.sub.5-6heterocycloalkyl,
particularly pyrrolidinyl or morpholinyl; and [0101] m is 1; and
[0102] R.sub.1 is meta or para to the sulfonamide, preferably para
to the sulfonamide; and [0103] n is 0 (so there is no R.sub.2 group
present); and [0104] X is CH.sub.2; and [0105] R.sub.3 is hydrogen;
and [0106] R.sub.4 is hydrogen; and [0107] W is N.
[0108] Examples of such compounds are shown below:
##STR00008##
[0109] Other particular compounds of Formula (I) and Formula (II)
include those wherein: [0110] R.sub.1 is optionally substituted
heteroaryl, particularly unsubstituted heteroaryl, most preferably
oxazolyl; and [0111] m is 1; and [0112] R.sub.1 is meta or para to
the sulfonamide, preferably para to the sulfonamide; and [0113] n
is 0 (so there is no R.sub.2 group present); and [0114] X is
CH.sub.2; and [0115] R.sub.3 is hydrogen; and [0116] R.sub.4 is
hydrogen; and [0117] W is N.
[0118] An example of such a compound is Compound 1 shown below:
##STR00009##
[0119] Other particular compounds of Formula (I) and Formula (II)
include those wherein: [0120] R.sub.1 is butyl (particularly
tert-butyl); and [0121] m is 1; and [0122] R.sub.1 is meta or para
to the sulfonamide, preferably para to the sulfonamide; and [0123]
n is 0 (so there is no R.sub.2 group present); and [0124] X is a
direct bond; and [0125] R.sub.3 is optionally substituted
heteroaryl, particularly unsubstituted heteroaryl such as pyridyl;
and [0126] R.sub.4 is hydrogen; and [0127] W is N. [0128] An
example of such a compound is shown below:
##STR00010##
[0129] Further particular compounds of Formula (I) and Formula (II)
include those wherein: [0130] R.sub.1 is tert-butyl,
trifluoromethyl, trifluoromethoxy, difluoromethoxy (, or methoxy;
and [0131] m is 1; and [0132] R.sub.1 is meta or para to the
sulfonamide, preferably para to the sulfonamide; and [0133] n is 0
(so there is no R.sub.2 group present); and [0134] X is a direct
bond; and [0135] R.sub.3 is cyclopropyl; and [0136] R.sub.4 is
hydrogen; and [0137] W is N. [0138] Examples of such compounds are
shown below:
##STR00011## ##STR00012##
[0139] Further particular compounds of Formula (I) and Formula (II)
include those wherein: [0140] R.sup.1 is halo (such as bromo),
tert-butyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy;
and [0141] m is 1; and [0142] R.sub.1 is meta or para to the
sulfonamide, preferably para to the sulfonamide; and [0143] n is 0
(so there is no R.sub.2 group present); and [0144] X is CH.sub.2,
CH.sub.2CH.sub.2, or C(CH.sub.3)(CH.sub.3); and [0145] R.sub.3 is
hydrogen; and [0146] R.sub.4 is hydrogen; and [0147] W is N. [0148]
Examples of such compounds are shown below:
##STR00013##
[0149] Especially preferred examples of such compounds are shown
below:
##STR00014##
[0150] Preferred compounds of Formula (I) are compounds of Formula
(II) wherein: [0151] m is 1; and [0152] R.sub.1 is butyl
(particularly tert-butyl); and [0153] R.sub.1 is meta or para to
the sulfonamide, preferably para to the sulfonamide; and [0154] n
is 0 (so there is no R.sub.2 group present); and [0155] XR.sub.3 is
selected from methyl, cyclopropyl, optionally substituted pyridyl,
optionally substituted thiophenyl, optionally substituted
pyrazolyl, optionally substituted pyridazinyl, optionally
substituted oxazolyl, and optionally substituted pyrrolyl,
including pyridyl, cyano-pyridyl, fluoro-pyridyl, methoxy-pyridyl,
pyridine-N oxide, methoxy-pyridine-N oxide, ethoxy-pyridyl,
ethoxy-pyridyl N-oxide, methyl-pyridyl and methyl-pyridyl N-oxide,
thiophenyl-CO.sub.2H, pyrazolyl, methyl-pyrazolyl,
dimethyl-pyrazolyl, pyridazinyl, oxazolyl, and methyl-pyrrolyl;
most preferably XR.sub.3 is selected from methyl, optionally
substituted pyridyl, optionally substituted thiophenyl, optionally
substituted pyrazolyl, and optionally substituted pyrrolyl,
including pyridyl, fluoro-pyridyl, methoxy-pyridyl, pyridine-N
oxide, methoxy-pyridyl-N oxide, ethoxy-pyridyl, ethoxy-pyridyl
N-oxide, methyl-pyridyl, methyl-pyridyl N-oxide,
thiophenyl-CO.sub.2H, pyrazolyl, methyl-pyrazolyl, and
methyl-pyrrolyl; [0156] R.sub.4 is hydrogen; and [0157] W is
C-chloro or C-cyano. [0158] Examples of such a compound are shown
below:
##STR00015## ##STR00016##
[0159] Other preferred compounds of Formula (I) are compounds of
Formula (II) wherein: [0160] m is 1; and [0161] R.sub.1 is butyl
(particularly tert-butyl); and [0162] R.sub.1 is meta or para to
the sulfonamide, preferably para to the sulfonamide; and [0163] n
is 1; and [0164] R.sub.2 is halo (such as chloro) or CN,
particularly CN; and [0165] the R.sub.2 group is ortho to the
sulfonamide; and [0166] XR.sub.3 is selected from methyl,
cyclopropyl, optionally substituted pyridyl, optionally substituted
thiophenyl, optionally substituted pyrazolyl, optionally
substituted pyridazinyl, optionally substituted oxazolyl, and
optionally substituted pyrrolyl, including pyridyl, cyano-pyridyl,
fluoro-pyridyl, methoxy-pyridyl, pyridine-N oxide,
methoxy-pyridine-N oxide, methoxy-pyridine-N oxide, ethoxy-pyridyl,
ethoxy-pyridyl N-oxide, methyl-pyridyl and methyl-pyridyl N-oxide,
thiophenyl-CO.sub.2H, pyrazolyl, methyl-pyrazolyl,
dimethyl-pyrazolyl, pyridazinyl, oxazolyl, and methyl-pyrrolyl;
most preferably XR.sub.3 is selected from methyl, optionally
substituted pyridyl, optionally substituted thiophenyl, optionally
substituted pyrazolyl, and optionally substituted pyrrolyl,
including pyridyl, fluoro-pyridyl, methoxy-pyridyl, pyridine-N
oxide, methoxy-pyridyl-N oxide, ethoxy-pyridyl, ethoxy-pyridyl
N-oxide, methyl-pyridyl, methyl-pyridyl N-oxide,
thiophenyl-CO.sub.2H, pyrazolyl, methyl-pyrazolyl, and
methyl-pyrrolyl; [0167] R.sub.4 is hydrogen; and [0168] W is CH.
[0169] An example of such a compound is shown below:
##STR00017##
[0170] It will be appreciated that, in the compounds described
above: [0171] R.sub.1 is trifluoromethoxy when R.sub.1 is
Z.sub.q1B, q.sub.1 is 2, the first Z group is O, the second Z group
is CR.sub.5R.sub.6, and each of R.sub.5, R.sub.6 and B is fluoro;
[0172] R.sub.1 is trifluoromethyl when R.sub.1 is Z.sub.q1B,
q.sub.1 is 1, Z is CR.sub.5R.sub.6, and each of R.sub.5, R.sub.6
and B is fluoro; [0173] R.sub.1 is tert-butyl when R.sub.1 is
Z.sub.q1B, q.sub.1 is 2, the first Z group is CR.sub.5R.sub.6 where
each of R.sub.5 and R.sub.6 is methyl, the second Z group is
CR.sub.5R.sub.6 where each of R.sub.5 and R.sub.6 is hydrogen, and
B is hydrogen; [0174] R.sub.1 is isopropyl when R.sub.1 is
Z.sub.q1B, q.sub.1 is 1, the Z group is CR.sub.5R.sub.6 where each
of R.sub.5 and R.sub.6 is methyl, and B is hydrogen; or R.sub.1 is
isopropyl when R.sub.1 is Z.sub.q1B, q.sub.1 is 2, the first Z
group is CR.sub.5R.sub.6 where one of R.sub.5 and R.sub.6 is methyl
and the other is H, the second Z group is CR.sub.5R.sub.6 where
each of R.sub.5 and R.sub.6 is hydrogen, and B is hydrogen; [0175]
R.sub.1 is methyl when R.sub.1 is Z.sub.q1B, q.sub.1 is 1, the Z
group is CR.sub.5R.sub.6 where each of R.sub.5 and R.sub.6 is
hydrogen, and B is hydrogen; [0176] R.sub.1 is difluoromethoxy when
R.sub.1 is Z.sub.q1B, q.sub.1 is 2, the first Z group is O, the
second Z group is CR.sub.5R.sub.6, one of R.sub.5, R.sub.6 and B is
hydrogen, and two of R.sub.5, R.sub.6 and B are fluoro; [0177]
R.sub.1 is methoxy when R.sub.1 is Z.sub.q1B, q.sub.1 is 2, the
first Z group is O, the second Z group is CR.sub.5R.sub.6 where
each of R.sub.5 and R.sub.6 is hydrogen, and B is hydrogen; [0178]
R.sub.1 is carboxy-methyl, (CO)CH.sub.3 when R.sub.1 is Z.sub.q1B,
q.sub.1 is 2, the first Z group is CO, the second Z group is
CR.sub.5R.sub.6 where each of R.sub.5 and R.sub.6 is hydrogen, and
B is hydrogen; [0179] R.sub.1 is methyl sulfonyl, SO.sub.2CH.sub.3
when R.sub.1 is Z.sub.q1B, q.sub.1 is 2, the first Z group is
SO.sub.2, the second Z group is CR.sub.5R.sub.6 where each of
R.sub.5 and R.sub.6 is hydrogen, and B is hydrogen; [0180] R.sub.1
is (CH.sub.2).sub.3OCH.sub.3 when R.sub.1 is Z.sub.q1B, q.sub.1 is
5, each of the first three Z groups and the fifth Z group is
CR.sub.5R.sub.6 where each of R.sub.5 and R.sub.6 is hydrogen, the
fourth Z group is O, and B is hydrogen; [0181] R.sub.1 is
C(CH.sub.3)(CH.sub.3)CN when R.sub.1 is Z.sub.q1B, q.sub.1 is 1,
the Z group is CR.sub.5R.sub.6 where each of R.sub.5 and R.sub.6 is
methyl, and B is cyano.
[0182] Specific compounds of the invention include the compounds of
Formula (I) listed in Table 1, and any salt or solvate thereof,
including a solvate of such a salt:
TABLE-US-00001 TABLE 1 Compound number Structure 1 ##STR00018## 2
##STR00019## 3 ##STR00020## 4 ##STR00021## 5 ##STR00022## 6
##STR00023## 7 ##STR00024## 8 ##STR00025## 9 ##STR00026## 10
##STR00027## 11 ##STR00028## 12 ##STR00029## 13 ##STR00030## 14
##STR00031## 15 ##STR00032## 16 ##STR00033## 17 ##STR00034## 18
##STR00035## 19 ##STR00036## 20 ##STR00037## 21 ##STR00038## 22
##STR00039## 23 ##STR00040## 24 ##STR00041## 25 ##STR00042## 26
##STR00043## 27 ##STR00044## 28 ##STR00045## 29 ##STR00046## 30
##STR00047## 31 ##STR00048## 32 ##STR00049## 33 ##STR00050## 34
##STR00051## 35 ##STR00052## 36 ##STR00053## 37 ##STR00054## 38
##STR00055## 39 ##STR00056## 40 ##STR00057## 41 ##STR00058## 42
##STR00059## 43 ##STR00060## 44 ##STR00061## 45 ##STR00062## 46
##STR00063## 47 ##STR00064## 48 ##STR00065## 49 ##STR00066## 50
##STR00067## 51 ##STR00068## 52 ##STR00069## 53 ##STR00070## 54
##STR00071## 55 ##STR00072## 56 ##STR00073## 57 ##STR00074## 58
##STR00075## 59 ##STR00076## 60 ##STR00077## 61 ##STR00078## 62
##STR00079## 63 ##STR00080## 64 ##STR00081## 65 ##STR00082## 66
##STR00083## 67 ##STR00084## 68 ##STR00085## 69 ##STR00086## 70
##STR00087## 71 ##STR00088## 72 ##STR00089## 73 ##STR00090## 74
##STR00091## 75 ##STR00092## 76 ##STR00093## 77 ##STR00094## 78
##STR00095## 79 ##STR00096## 80 ##STR00097## 81 ##STR00098## 82
##STR00099## 83 ##STR00100## 84 ##STR00101## 85 ##STR00102## 86
##STR00103## 87 ##STR00104## 88 ##STR00105## 89 ##STR00106## 90
##STR00107## 91 ##STR00108## 92 ##STR00109## 93 ##STR00110## 94
##STR00111## 95 ##STR00112## 96 ##STR00113## 97 ##STR00114## 98
##STR00115## 99 ##STR00116## 100 ##STR00117## 101 ##STR00118## 102
##STR00119## 103 ##STR00120## 104 ##STR00121## 105 ##STR00122## 106
##STR00123## 107 ##STR00124## 108 ##STR00125## 109 ##STR00126## 110
##STR00127## 111 ##STR00128## 112 ##STR00129## 113 ##STR00130## 114
##STR00131## 115 ##STR00132## 116 ##STR00133## 117 ##STR00134## 118
##STR00135## 119 ##STR00136## 120 ##STR00137## 121 ##STR00138## 122
##STR00139## 123 ##STR00140##
124 ##STR00141## 125 ##STR00142## 126 ##STR00143## 127 ##STR00144##
128 ##STR00145## 129 ##STR00146## 130 ##STR00147## 131 ##STR00148##
132 ##STR00149## 133 ##STR00150## 134 ##STR00151## 135 ##STR00152##
136 ##STR00153## 137 ##STR00154## 138 ##STR00155## 139 ##STR00156##
140 ##STR00157## 141 ##STR00158## 142 ##STR00159## 143 ##STR00160##
144 ##STR00161## 145 ##STR00162## 146 ##STR00163## 147 ##STR00164##
148 ##STR00165## 149 ##STR00166## 150 ##STR00167## 151 ##STR00168##
152 ##STR00169## 153 ##STR00170## 154 ##STR00171## 155 ##STR00172##
156 ##STR00173## 157 ##STR00174## 158 ##STR00175## 159 ##STR00176##
160 ##STR00177## 161 ##STR00178## 162 ##STR00179## 163 ##STR00180##
164 ##STR00181## 165 ##STR00182## 166 ##STR00183## 167 ##STR00184##
168 ##STR00185## 169 ##STR00186## 170 ##STR00187## 171 ##STR00188##
172 ##STR00189## 173 ##STR00190## 174 ##STR00191## 175 ##STR00192##
176 ##STR00193## 177 ##STR00194## 178 ##STR00195## 179 ##STR00196##
180 ##STR00197## 181 ##STR00198## 182 ##STR00199## 183 ##STR00200##
184 ##STR00201## 185 ##STR00202## 186 ##STR00203## 187 ##STR00204##
188 ##STR00205## 189 ##STR00206## 190 ##STR00207## 191 ##STR00208##
192 ##STR00209## 193 ##STR00210## 194 ##STR00211## 195 ##STR00212##
196 ##STR00213## 197 ##STR00214## 198 ##STR00215## 199 ##STR00216##
200 ##STR00217## 201 ##STR00218## 202 ##STR00219## 203 ##STR00220##
204 ##STR00221## 205 ##STR00222## 206 ##STR00223## 207 ##STR00224##
208 ##STR00225## 209 ##STR00226## 210 ##STR00227## 211
##STR00228##
[0183] The compound of Formula (I) may be used as such, or in the
form of a salt or solvate thereof, including a solvate of such a
salt. Preferably a salt or solvate is one which is pharmaceutically
acceptable.
[0184] Suitable salts of the compound of Formula (I) include metal
salts, for example alkali metal or alkaline earth metal salts, for
example sodium, potassium, calcium and magnesium salts; or salts
with ammonia, primary, secondary or tertiary amines, or amino
acids, for example mono-, di- or tri-alkylamines,
hydroxyalkylamines, and nitrogen-containing heterocyclic compounds,
for example isopropylamine, trimethylamine, diethylamine,
tri(i-propyl)amine, tri(n-propyl)amine, ethanolamine,
2-dimethylaminoethanol, lysine, histidine, arginine, choline,
caffeine, glucamine, procaine, hydrabamine, betaine,
ethylenediamine, N-alkylglucamines, theobromine, purines,
piperazine, piperidine, morpholine, n-alkyl piperidines, etc; or
salts such as trifluoroacetic acid (TFA) salt. For example,
pharmaceutically acceptable salts of a compound of Formula (I)
include acid addition salts such as hydrochloride, hydrobromide,
citrate, tartrate and maleate salts and salts formed with
phosphoric and sulphuric acid. In another aspect suitable
pharmaceutically acceptable salts are base salts such as an alkali
metal salt for example sodium or potassium, an alkaline earth metal
salt for example calcium or magnesium, or organic amine salt for
example triethylamine.
[0185] Many organic compounds can form complexes with solvents in
which they are reacted or trom which they are precipitated or
crystallized. These complexes are known as solvates. For example, a
complex with water is known as a hydrate. Such solvates form part
of the invention.
[0186] The compound of Formula (I) or its salt or solvate
(including a solvate of such a salt) may itself act as a prodrug,
or may be converted into a prodrug by known methods. A further
aspect of the invention provides a prodrug of the compound of
Formula (I) or its salt or solvate (including a solvate of such a
salt). Pharmaceutically acceptable prodrugs are described in T.
Higuchi and V. Stella (Prodrugs as novel delivery systems, vol 14
of the ACS Symposium Series), and in Edward B. Roche, ed.
(Bioreversible carriers in drug design, American Pharm Assoc and
Pergamon Press, 1987), both of which are incorporated herein by
reference. In one embodiment, a prodrug is a compound having a
group that is cleavable from the molecule to generate a
biologically active form. Thus the prodrug may be converted within
the body into an active form or an active metabolite or residue
thereof, due to the presence of particular enzymes or conditions
that cleave the prodrug molecule. The cleavable group within the
prodrug may be linked by any suitable bond, such as an ester bond
or an amide bond (derived from any suitable amine, for example a
mono-, di- or tri-alkylamine, or any of the amines mentioned
above). For example, the prodrug may be an in vivo hydrolysable
ester, such as an ester of a CO.sub.2H group present in the
compound of Formula (I) with any suitable alcohol, for example a
C.sub.1-6alkanol. Alternatively, it may be an ester of any --OH
group present in the compound of Formula (I) with any suitable
acid, for example any carboxylic or sulfonic acid. Prodrugs that
are in vivo hydrolysable esters of a compound of Formula (I) are
pharmaceutically acceptable esters that hydrolyse in the human body
to produce the parent compound. Such esters can be identified by
administering, for example intravenously, to a test animal, the
compound under test and subsequently examining the test animal's
body fluids. Suitable in vivo hydrolysable esters for carboxy
include methoxymethyl and for hydroxy include formyl and acetyl,
especially acetyl.
[0187] The present invention also provides a process for the
preparation of a compound of Formula (I), which comprises a process
according to Scheme 1 or Scheme 2 or Scheme 3 or Scheme 4, as
described below.
[0188] The present invention provides a process for the preparation
of a compound of Formula (I) wherein n is 0, which comprises
converting cyanoacetic acid (A) to cyanoenamine (B) by treatment
with diethylamine, treating the cyanoenamine (B) with a pyrazole
amine (D) to produce an amino substituted pyrazolopyrimidine (E),
then: [0189] (i) converting the amino substituted
pyrazolopyrimidine (E) to a secondary sulfonamide (J) using a
sulfonyl chloride (F), and optionally derivatising the secondary
sulfonamide (J) to a tertiary sulfonamide (K) using a base and an
appropriate alkyl halide; or [0190] (ii) converting the amino
substituted pyrazolopyrimidine (E) to a secondary amine (G) using a
base and an appropriate alkyl halide, then converting the secondary
amine (G) to the tertiary sulfonamide (K) using a sulfonyl chloride
(F); or [0191] (iii) condensing the amino substituted
pyrazolopyrimidine (E) and a sulfonyl chloride (F) to a
di-substituted sulfonamide (H), then converting the di-substituted
sulfonamide (H) to the secondary sulfonamide (J), and optionally
derivatising the secondary sulfonamide (H) to a tertiary
sulfonamide (J) using a base and an appropriate alkyl halide; and
[0192] (iv) optionally adding appropriate substituents to an
R.sub.1 or R.sub.3 group of the secondary sulfonamide (J) or of the
tertiary sulfonamide (K);
[0193] as shown in Scheme 1 below, wherein R.sub.1, X, R.sub.3,
R.sub.4 and m have the meanings given for the general Formula (I),
and Z is a halogen atom (most likely bromine):
##STR00229##
[0194] The cyanoacetic acid of formula A may be converted to the
cyanoenamine of formula B by treatment with diethylamine in a
solvent such as triethyl orthoformate. This may be treated with a
pyrazole amine, D, in a suitable base such as pyridine to produce
an amino substituted pyrazolopyrimidine E. This may either be
converted to the secondary sulfonamide J which may then, if
desired, be derivatised to the tertiary sulfonamide K or it may
first be converted to the secondary amine G, before conversion to
the tertiary sulfonamide K. Conversion of the compounds of formula
E or G to the compounds of formula J or K respectively may be
achieved by the use of a sulfonyl chloride F. This reagent is
either used with a base such as pyridine, triethylamine or
diisopropylethylamine in the presence or absence of a catalytic
quantity of an agent such as dimethylaminopyridine and using a
solvent such as dichloromethane, or by the use of sodium hydride as
base in a dipolar aprotic solvent such as DMF prior to addition of
the sulfonyl chloride. Conversion of the compounds of formula E or
J to the compounds of formula G or K respectively may be achieved
by the use of a base such as sodium hydride followed by the
appropriate alkyl halide. Condensation of compounds of formula E
and F in the presence of base may sometimes proceed to the
di-substituted sulfonamide H. In this case, the desired product J
may be prepared by use of an agent such as tetrabutyl ammonium
fluoride in a solvent such as THF.
[0195] The present invention further provides a process for the
preparation of a compound of Formula (I) wherein n is 1 or 2, which
comprises reacting a pyrazole amine (D) with a dimethyl acetal (M)
to produce a pyrazole imidamide (N), treating the pyrazole
imidamide (N) with a nitrile to form a pyrazolo pyridine (P), then:
[0196] (i) converting the pyrazolo pyridine (P) to a secondary
sulfonamide (R) using a sulfonyl chloride (F), and optionally
derivatising the secondary sulfonamide (P) to a tertiary
sulfonamide (S) using a base and an appropriate alkyl halide; or
[0197] (ii) converting the pyrazolo pyridine (P) to a secondary
amine (Q) using a base and an appropriate alkyl halide, then
converting the secondary amine (Q) to a tertiary sulfonamide (S)
using a sulfonyl chloride (F); and [0198] (iii) optionally adding
appropriate substituents to an R.sub.1 or R.sub.3 group of the
secondary sulfonamide (R) or of the tertiary sulfonamide (S);
[0199] as shown in Scheme 2 below, wherein R.sub.1, R.sub.2, X,
R.sub.3, R.sub.4 and m have the meanings given for the general
Formula (I), and Z is a halogen atom (most likely bromine):
##STR00230##
[0200] When R.sub.2 is present in a compound of Formula I (that is,
when n=1 or 2), the compounds may be prepared as shown in Scheme 2.
The pyrazole amine D may be reacted with the dimethyl acetal M in a
solvent such as xylene to produce the pyrazole imidamide N. This on
treatment with a nitrile in the presence of an organic base such as
piperidine and a solvent, for example ethanol, results in the
formation of a pyrazolo pyridine P. This may either be converted to
the secondary sulfonamide R which may then, if desired, be
derivatised to the tertiary sulfonamide S or it may first be
converted to the secondary amine Q, before conversion to the
tertiary sulfonamide S. Conversion of the compounds of formula P or
Q to the compounds of formula R or S respectively may be achieved
by the use of a sulfonyl chloride F. This reagent is either used
with a base such as pyridine, triethylamine or
diisopropylethylamine in the presence or absence of a catalytic
quantity of an agent such as dimethylaminopyridine and using a
solvent such as dichloromethane, or by the use of sodium hydride as
base in a dipolar aprotic solvent such as DMF prior to addition of
the sulfonyl chloride. Conversion of the compounds of formula P or
R to the compounds of formula Q or S respectively may be achieved
by the use of a base such as sodium hydride followed by the
appropriate alkyl halide.
[0201] The present invention also provides a process for the
preparation of a compound of Formula (I) wherein W is CR.sub.10,
which comprises the steps shown in either Scheme 3 or Scheme 4
below.
[0202] The present invention provides a process for the preparation
of a compound of Formula (I) wherein W is CR.sub.10, which
comprises: [0203] (i) converting aminopyridine (T) to sulfonamide
(U) by the use of a sulfonyl chloride (F); [0204] (ii) treating the
sulfonamide (U) with an acetylene moiety (Y) in the presence of
coupling reagents to produce pyridine acetylene (Z); [0205] (iii)
converting the pyridine acetylene (Z) by treatment with
mesitlyenesulfonylhydroxylamine (AA) to an aminopyridinium salt
(AB); [0206] (iv) treating the aminopyridinium salt (AB) with a
base to produce pyrazolopyridine (AC);
[0207] as shown in Scheme 3 below, wherein R.sub.1, R.sub.2, X,
R.sub.3, R.sub.4, R.sub.10 and m have the meanings given for the
general Formula (I):
##STR00231##
[0208] In Scheme 3 the aminopyridine of formula T may be converted
to the sulfonamide of formula U by the use of a sulfonyl chloride
F. This reagent is either used with a base such as pyridine,
triethylamine or diisopropylethylamine in the presence or absence
of a catalytic quantity of an agent such as dimethylaminopyridine
and using a solvent such as dichloromethane, or by the use of
sodium hydride as base in a dipolar aprotic solvent such as DMF
prior to addition of the sulfonyl chloride. Treatment of U with an
acetylene moiety Y in the presence of coupling reagents such as a
mixture of Bis(triphenylphosphine)palladium(II) chloride,
copper(I)iodide and triethylamine in a solvent such as DMF will
give rise to the pyridine acetylene Z. On treatment with
mesitlyenesulfonylhydroxylamine AA, Z may be converted to an
aminopyridinium salt of formula AB which on treatment with a base
such as potassium carbonate will ring close to produce the
pyrazolopyridine AC.
[0209] The present invention also provides a process for the
preparation of a compound of Formula (I) wherein W is CR.sub.10,
which comprises: [0210] (i) coupling an aminopyridine (AD or AH)
with sulfonyl chloride (F) to produce pyridine sulfonamide (AE or
AJ); [0211] (ii) deprotonating the pyridine sulfonamide (AE) with a
base in a suitable solvent, and quenching the resulting anion with
an ester or activated amide of formula AF, to form ketone (AG); or
converting the pyridine sulfonamide (AJ) to ketone (AG) by
treatment with suitable reagents and a compound of formula AK;
[0212] (iii) converting the ketone (AG) to oxime (AL) using
hydroxylamine hydrochloride in a suitable solvent; [0213] (iv)
dehydrating oxime (AL) using a dehydrating agent to produce azirine
(AM); [0214] (v) rearranging the azirine (AM) using ferrous
chloride to produce a compound of formula AN;
[0215] as shown in Scheme 4 below, wherein R.sub.1, R.sub.2, X,
R.sub.3, R.sub.4, R.sub.10 and m have the meanings given for the
general Formula (I):
##STR00232##
[0216] Scheme 4 may be used as an alternative route to Scheme 3. In
Scheme 4, the aminopyridine AD or AH may be coupled with the
sulfonyl chloride F under conditions as described for the
equivalent reaction described in Scheme 3. The resulting pyridine
sulfonamide AE may be deprotonated with a base such as sodium
bis(trimethylsilyl)amide in a solvent such as THF and the resulting
anion quenched with a species of formula AF (wherein LG may for
example be an alcohol such that AF is an ester, or it may be a
species such as N-methoxy-methylamine so that AF is an activated
amide). The pyridine sulfonamide AJ on the other hand is converted
to AG by treatment with reagents such as mixtures of
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, palladium(II)
acetate and potassium phosphate in a suitable solvent such as
dioxan. The resulting ketone AG can then be converted to the oxime
AL using hydroxylamine hydrochloride in a suitable solvent.
Dehydration of AL can be carried out using a dehydrating agent such
as trifluoroacetic anhydride and triethylamine in DME or similar as
solvent to afford the azirine AM which can then be rearranged using
iron (II) chloride or similar to the compound of formula AN.
[0217] All the above schemes comprehend that interconversion
between R groups can be carried out by normal means. For example if
R.sub.10 is a nitrile, this can be introduced into the species AC
and AN by treatment of a molecule where R.sub.10 is a halogen with
agents such as mixtures of Zn(CN).sub.2, 1, 1'-Bis
(diphenylphosphino)ferrocene, Pd.sub.2dba.sub.3, catalytic
quantities of Zn dust in solvents such as DMF and at elevated
temperatures. Similarly in the event that XR.sub.3 is pyridyl, this
may be converted to the corresponding N-oxide by treatment with
metachloroperoxybenzoic acid in a solvent such as dichloromethane
as a final step from structures J or K in Scheme 1, structures R or
S in Scheme 2 or structures AC or AK in schemes 3 and 4
respectively.
[0218] If protecting groups are required to allow certain
functional groups to be carried through transformations elsewhere
in a molecule, these can be introduced and removed by standard
means. Thus in the Schemes above, as well as corresponding to the
definitions in Formula 1, R.sub.1, X, R.sub.3, R.sub.4, and
R.sub.10 can also represent appropriately protected forms of these
groups.
[0219] It will be appreciated that many of the relevant starting
materials are commercially available or may be made by any
convenient method as described in the literature or known to the
skilled chemist or described in the Examples herein, or can be
prepared by methods analogous to such methods. For example,
reagents such as C or E may be commercially available or prepared
by routes as illustrated in the Examples herein by anyone skilled
in the art. Should R.sub.1 or XR.sub.3 contain functionality
requiring protection to allow the synthetic scheme to be carried
out, appropriate groups can be selected by anyone skilled in the
art. The structures of reagents C and E are shown below:
##STR00233##
[0220] In a further aspect of the invention, there is provided an
intermediate compound for use in the synthesis of a compound of
Formula (I). There is further provided the use of an intermediate
compound to synthesise a compound of Formula (I). Such intermediate
compounds include the intermediate compounds I-CXXXI disclosed in
the Examples herein and listed in Table 2.
TABLE-US-00002 TABLE 2 Intermediate compound number Disclosed in
Example number I 1 II 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12 III 1 IV 1
V 1 VI 1 VII 2 VIII 2 IX 2 X 2 XI 2, 3, 4, 5, 6, 7, 8, 10, 11, 12,
13, 14, 18, 26, 29, 30, 32 XII 2 XIII 3 XIV 3 XV 3 XVI 3 XVII 4
XVIII 4 XIX 4 XX 4 XXI 4 XXII 5 XXIII 5 XXIV 5 XXV 5 XXVI 5 XXVII 6
XXVIII 6 XXIX 6 XXX 6 XXXI 6 XXXII 7 XXXIII 7 XXXIV 7 XXXV 8 XXXVI
8 XXXVII 8 XXXVIII 9 XXXIX 9 XL 9 XLI 9 XLII 9 XLIII 10 XLIV 10 XLV
10, 15 XLVI 10 XLVII 10 XLVIII 10 XLIX 10 L 11 LI 11, 30 LII 11
LIII 11 LIV 11 LV 12 LVI 12 LVII 12 LVIII 12 LVIX 12 LX 13 LXI 13
LXII 13, 25, 32 LXIII 13 LXIV 13 LXV 13, 20, 25 LXVI 13 LXVII 13
LXVIII 14 LXIX 14, 15, LXX 14, 26, 27, 29 LXXI 14 LXXII 14 LXXIII
14 LXXV 15 LXXVI 15 LXXVII 15 LXXVIII 15 LXXIX 17, 22, 23, 24 LXXX
18, 30 LXXXI 18, 19, 21, 27, 30 LXXXII 18 LXXXIII 18 LXXXIV 18
LXXXV 18 LXXXVI 19 LXXXVII 19 LXXXVIII 19 LXXXIX 20 XC 20 XCI 20
XCII 20 XCIII 21 XCIV 21 XCV 21 XCVI 21 XCVII 21 XCVIII 22 XCIX 22
C 22 CI 22 CII 23 CIII 23 CIV 23 CV 23 CVI 24 CVII 24 CVIII 24 CIX
24 CX 25 CXI 25 CXII 25 CXIII 26 CXIV 26 CXV 26 CXVI 26 CXVII 26
CXVIII 27 CXIX 27 CXX 27 CXXI 29 CXXII 29 CXXIII 29 CXXIV 29 CXXV
30 CXXVI 30 CXXVII 30 CXXVIII 32 CXXIX 32 CXXX 32 CXXXI 32
[0221] A resulting compound of the invention may be converted into
any other compound of the invention by methods analogous to known
methods. For example: a resulting compound of Formula (I) may be
converted into a salt or solvate thereof; the oxidation state of an
atom in a heterocyclic ring may be increased or decreased by
oxidation or reduction using known methods; an ester may be
converted to the corresponding acid by hydrolysis (eg using an
aqueous hydroxide such as NaOH) or an acid maybe converted to a
corresponding metal salt (eg using an aqueous metal hydroxide, such
as NaOH to produce the sodium salt). During synthesis of any
compound of the invention, protecting groups may be used and
removed as desired.
[0222] The amount of the compound of the invention which is
required to achieve a therapeutic effect will, of course, depend
upon whether the effect is prophylactic or curative, and will vary
with the route of administration, the subject under treatment, and
the form of disease being treated. It is generally preferable to
use the lowest dose that achieves the desired effect. The compound
of the invention may generally be administered at a dose of from
0.1 to 1500 mg/kg per day, preferably 0.1 to 500 mg/kg per day,
typically from 0.5 to 20 mg/kg/day, for example about 3 mg/kg/day.
Unit dose forms may conveniently contain an amount of compound of
the invention which is effective at such dosage or as a multiple of
the same, for example units containing 5 mg to 500 mg, usually
around 10 mg to 200 mg.
[0223] For example, a pharmaceutical composition of this invention
may be administered to humans so that, for example, a daily dose of
0.5 to 20 mg/kg body weight (and preferably of 0.5 to 3 mg/kg body
weight) is received. This daily dose may be given in divided doses
as necessary, the precise amount of the compound received and the
route of administration depending on the weight, age and sex of the
patient being treated and on the particular disease or condition
being treated according to principles known in the art. Typically
unit dosage forms may contain about 1 mg to 500 mg of a compound of
Formula (I). For example, a unit dosage form containing up to 10
mg/kg may be given twice per day, such as 1.5 mg/kg twice per day
or 5 mg/kg twice per day or 10 mg/kg twice per day.
[0224] The compound of the present invention may be administered
one or more times per day, tor example, two or three times per day,
or even more often, for example, four or five times per day.
[0225] The compounds of this invention may be administered in
standard manner for the disease or condition that it is desired to
treat. For these purposes the compounds of this invention may be
formulated by means known in the art into the required form. While
it is possible for the active ingredient to be administered alone,
it is preferable for it to be present in a suitable composition
formulated as required. Suitable formulations according to the
invention include those suitable for oral (including sub-lingual),
parenteral (including subcutaneous, intradermal, intramuscular,
intravenous, and intraarticular), nasal, inhalation, topical
(including dermal, buccal, and sublingual), vaginal and rectal
administration. The most suitable route may depend upon, for
example, the nature and stage of the condition and disorder of the
recipient.
[0226] For oral administration, the compounds can be formulated as
liquids or solids. Forms suitable for oral administration include
for example tablets, capsules, pills, lozenges, granulates,
dragees, wafers, aqueous or oily solutions, suspensions, syrups, or
emulsions.
[0227] Forms suitable for parenteral use include for example
sterile aqueous or oily solutions or suspensions or sterile
emulsions or infusions.
[0228] Forms suitable for nasal administration include for example
drops, sprays and aerosols.
[0229] Forms suitable for inhalation include for example finely
divided powders, aerosols, fine particle dusts or mists which may
be generated by means of various types of metered dose pressurized
aerosols, nebulizers or insufflators.
[0230] Forms suitable for topical administration to the skin
include, for example, gels, creams, ointments, emulsions, pastes,
foams or adhesive patches. For female patients, the composition may
be in a form suitable for intravaginal administration.
[0231] Forms suitable for rectal administration include
suppositories, rectal capsules and enema solutions.
[0232] Forms suitable for transdermal administration generally
comprise an adjuvant that enhances the transdermal delivery of the
compound of the invention. Suitable adjuvants are known in the
art.
[0233] A pharmaceutical composition of the present invention may be
in unit dosage form. Suitable oral unit dosage forms include those
mentioned above. For administration by injection or infusion unit
dosage forms include, for example, vials and ampoules. Unit dosage
forms for topical administration to the skin include blister packs
or sachets, each blister or sachet containing a unit dose of, for
example, a gel, cream or ointment, for example, as described above.
A metered dosing device may be provided, for example, a pump
device, for dosing a predetermined volume of a topical composition,
for example, a cream, ointment or gel. A preparation may provide
delayed or sustained release, for example a depot preparation or an
adhesive patch.
[0234] Preferred formulations are those suitable for oral
administration, for example in the form of tablets, capsules, pills
or the like, or in the form of solutions suitable for injection
such as in water for injections BP or aqueous sodium chloride.
[0235] To make a composition according to the invention, suitable
carriers are well known in the art and include pharmaceutical grade
starch, mannitol, lactose, magnesium stearate, sodium saccharin,
talcum, cellulose, glucose, sucrose, (or other sugar), magnesium
carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water
(preferably sterile).
[0236] A liquid formulation will generally consist of a suspension
or solution of the compound or physiologically acceptable salt in a
suitable aqueous or non-aqueous liquid carrier(s), for example
water, ethanol, glycerine, polyethylene glycol or an oil. The
formulation may also contain a suspending agent, preservative,
flavouring or colouring agent.
[0237] A composition in the form of a tablet can be prepared using
any suitable pharmaceutical carrier(s) routinely used for preparing
solid formulations. Examples of such carriers include magnesium
stearate, starch, lactose, sucrose and microcrystalline
cellulose.
[0238] A composition in the form of a capsule can be prepared using
routine encapsulation procedures. For example, powders, granules or
pellets containing the active ingredient can be prepared using
standard carriers and then filled into a hard gelatin capsule;
alternatively, a dispersion or suspension can be prepared using any
suitable pharmaceutical carrier(s), for example aqueous gums,
celluloses, silicates or oils and the dispersion or suspension then
filled into a soft gelatin capsule.
[0239] Compositions for oral administration may be designed to
protect the active ingredient against degradation as it passes
through the alimentary tract, for example by an outer coating of
the formulation on a tablet or capsule.
[0240] Conveniently the composition is in unit dose form such as a
tablet or capsule.
[0241] In addition to the compounds of the present invention, the
pharmaceutical composition of this invention may also contain, or
be co-administered (simultaneously or sequentially) with, one or
more pharmacological agents of value in treating one or more
diseases or conditions referred to hereinabove. For example,
pharmaceutical compositions as described above may also comprise
one or more further active ingredients in addition to a compound of
the invention, for example, a further active ingredient with
efficacy in the treatment or prevention of IBD or of conditions
associated with IBD.
[0242] The compounds of the invention are compounds which modulate
at least one function or characteristic of mammalian CCR9, for
example, a human CCR9 protein. The ability of a compound to
modulate the function of CCR9 can be demonstrated in a binding
assay (such as a ligand binding or agonist binding assay), a
migration assay, a signaling assay (such as activation of a
mammalian G protein, induction of rapid and transient increase in
the concentration of cytosolic free calcium) and/or cellular
response assay (such as stimulation of chemotaxis, exocytosis or
inflammatory mediator release by leukocytes). In particular,
compounds of the invention may be evaluated in one or more of the
following assays: (1) human CCR9 FLIPR assay using recombinant cell
lines expressing human CCR9 or MOLT-4 cells (for example,
identifying active compounds as those having K.sub.i.ltoreq.10
.mu.M, preferred compounds as those having K.sub.i.ltoreq.1 .mu.M)
and most preferred compounds as those having a K.sub.i.ltoreq.500
nM); (2) chemotaxis assay using MOLT-4 cells (for example,
identifying active compounds as those having K.sub.i.ltoreq.10
.mu.M, preferred compounds as those having K.sub.i.ltoreq.1 .mu.M
and most preferred compounds as those having a K.sub.i.ltoreq.500
nM); (3) chemotaxis assay using mouse and rat thymocytes (for
example, identifying active compounds as those having
K.sub.i.ltoreq.1 .mu.M, and preferred compounds as those having
K.sub.i.ltoreq.500 nM and most preferred compounds as those having
a K.sub.i.ltoreq.500 nM).
[0243] As previously outlined the compounds of the invention are
CCR9 modulators, in particular they are partial agonists,
antagonists or inverse agonists of CCR9. Each of the above
indications for the compounds of the Formula (I) represents an
independent and particular embodiment of the invention. Whilst we
do not wish to be bound by theoretical considerations, some of the
preferred compounds of the invention may show selective CCR9
modulation for any one of the above indications relative to
modulating activity against any other particular receptor,
including any other particular chemokine receptor (for example,
CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR10, CXCR1,
CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, CX3CR.sub.1, XCR1,
ChemR.sub.23 or CMKLR.sub.1); by way of non-limiting example they
may show 100-1000 fold selectivity for CCR9 over activity against
any other particular chemokine receptor.
[0244] The invention will now be illustrated but not limited by the
following Examples. Each exemplified compound represents a
particular and independent aspect of the invention.
[0245] Where optically active centres exist in the compounds of
Formula (I), we disclose all individual optically active forms and
combinations of these as individual specific embodiments of the
invention, as well as their corresponding racemates.
[0246] Analytical TLC was performed on Merck silica gel 60
F.sub.254 aluminium-backed plates. Compounds were visualised by UV
light and/or stained either with iodine, potassium permanganate or
ninhydrin solution. Flash column chromatography was performed on
silica gel (100-200 M) or flash chromatography. .sup.1H-NMR spectra
were recorded on a Bruker Avance-400 MHz spectrometer with a BBO
(Broad Band Observe) and BBFO (Broad Band Fluorine Observe) probe.
Chemical shifts (.delta.) are expressed in parts per million (ppm)
downfield by reference to tetramethylsilane as the internal
standard. Splitting patterns are designated as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet) and bs (broad
singlet). Coupling constants (J) are given in hertz (Hz). LC-MS
analyses were performed on either an Acquity BEH C-18 column
(2.10.times.100 mm, 1.70 .mu.m) or on a Acquity HSS-T3 column
(2.10.times.100 mm, 1.80 .mu.m) using the Electrospray Ionisation
(ESI) technique. Purity assessment for final compounds was based on
the following 2 LCMS methods. Method 1 consisted of the following:
Acquity BEH C-18 column 2.10 mm.times.100 mm, 1.70 .mu.m. Mobile
phase; A, 5 mM ammonium acetate in water; B, acetonitrile;
gradient, 90% A to 10% A in 8 min with 10 min run time and a flow
rate of 0.3 mL/min. Method 2 consisted of the following: Acquity
HSS-T3 column 2.10 mm.times.100 mm, 1.8 .mu.m. Mobile phase; A,
0.1% TFA in water; B, acetonitrile; gradient, 90% A to 10% A in 8
min with 10 min run time and a flow rate of 0.3 mL/min.
Example 1
Synthesis of Compound 1
[N-(2-methylpyrazolo[1,5-a]pyrimidin-7-yl)-4-(oxazol-5-yl)benzenesulfonam-
ide] and Compounds 2-36
##STR00234##
[0248] Synthesis of II:
[0249] A mixture of cyanoacetic acid (I; 20 g, 235 mmol),
triethylorthoformate (34.04 g; 235 mmol) and diethylamine (17.17 g;
235 mmol) was heated at 140.degree. C. for 3 hours. The reaction
mixture was concentrated at reduced pressure and then diluted with
a saturated solution of sodium bicarbonate. The organic layer was
extracted with ethyl acetate, which was washed with water, brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum
to afford crude solid (II; 15 g;), which was used in the next step
without further purification.
[0250] Synthesis of IV:
[0251] To a stirred solution of 5-methyl-1H-pyrazol-3-amine (III; 5
g; 51.5 mmol) in pyridine (60 mL) was added
3-(diethylamino)acrylonitrile (II; 9.6 g; 77 mmol). The reaction
mixture was heated at 120.degree. C. for 14 hours and then cooled
and concentrated under reduced pressure. The crude mixture was
purified by column chromatography using 2% MeOH-DCM to obtain
2-methylpyrazolo[1,5-a]pyrimidin-7-amine as a brown solid (IV; 3 g;
39.3% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 7.97-7.96 (d,
J=5.2 Hz, 1H), 7.58 (bs, 2H), 6.14 (s, 1H), 5.98-5.97 (d, J=5.2 Hz,
1H), 2.38 (s, 3H). MS (M+1): 149.2.
Synthesis of Compound 1;
N-(2-methylpyrazolo[1,5-a]pyrimidin-7-yl)-4-(oxazol-5-yl)benzenesulfonami-
de
[0252] To a stirred solution of
2-methylpyrazolo[1,5-a]pyrimidin-7-amine, (IV; 100 mg; 0.67 mmol)
in chloroform (10 mL) was added pyridine (160 mg; 2.02 mmol) and
4-(oxazol-5-yl)benzene-1-sulfonyl chloride (V; 246 mg; 1.01 mmol)
at 0.degree. C. The reaction mixture was heated at 80.degree. C.
for 14 hours. The reaction mixture was cooled and concentrated at
reduced pressure to afford the di-substituted sulfonamide product
the structure of which was confirmed by LCMS (vi; 90% purity). The
crude product was dissolved in THF (5 mL) in presence of TBAF (0.5
mL) and stirred at room temperature for 2 hours. The reaction
mixture was concentrated at reduced pressure, diluted with water
and the aqueous layer was extracted with EtOAc (3.times.25 mL). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford the crude
compound, which was purified by column chromatography (4%
MeOH-DCM)) to obtain the title compound
N-(2-methylpyrazolo[1,5-a]pyrimidin-7-yl)-4-(oxazol-5-yl)benzenesulfonami-
de (1; 25 mg; 11% yield). .sup.1HNMR (400 MHz, DMSO-d6): .delta.
13.46 (bs, 1H), 8.54 (s, 1H), 8.04-8.02 (d, J=7.2 Hz, 1H),
7.97-7.95 (d, J=8.4 Hz, 2H), 7.91-7.88 (d, J=8.4 Hz, 2H), 7.85 (s,
1H), 6.65-6.63 (d, J=7.2 Hz, 1H), 6.62 (s, 1H), 2.33 (s, 3H). MS
(M+1): 356.07. (LCMS purity 94.37%, 4.19 min) (2).
[0253] The Following Compounds were Prepared in Essentially the
Same Manner Using the Appropriate Sulfonyl Chloride in the Final
Step:
TABLE-US-00003 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
2 ##STR00235## 331.12 96.13%, Rt = 5.26 min (2) .sup.1HNMR (400
MHz, DMSO- d6): .delta. 13.28 (bs, 1H), 8.01- 7.99 (d, J = 7.0 Hz,
1H), 7.79-7.77 (d, J = 8.0 Hz, 2H), 7.42-7.40 (d, J = 8.0 Hz, 2H),
6.65-6.63 (d, J = 7.0 Hz, 1H), 6.19 (s, 1H), 2.98-2.91 (m, 1H),
2.32 (s, 3H), 1.20-1.19 (d, J = 6.8 Hz, 6H). 3 ##STR00236## 345.13
98.57%, Rt = 5.45 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta.
13.20 (bs, 1H), 7.99- 7.97 (d, J = 6.8 Hz, 1H), 7.79-7.77 (d, J =
8.4 Hz, 2H), 7.57-7.54 (d, J = 8.4 Hz, 2H), 6.63-6.61 (d, J = 6.8
Hz, 1H), 6.17 (s, 1H), 2.32 (s, 3H), 1.28 (s, 9H). 4 ##STR00237##
391.02 98.49%, Rt = 5.52 min (2) .sup.1HNMR (400 MHz, DMSO- d6):
.delta. 13.52 (bs, 1H), 8.17- 8.15 (m, 2H), 8.07-8.05 (d, J = 6.8
Hz, 1H), 7.94-7.92 (d, J = 5.6 Hz, 1H), 6.62-6.60 (d, J = 7.2 Hz,
1H), 6.23 (s, 1H), 2.33 (s, 3H). 5 ##STR00238## 319.11 99.45%, Rt =
4.32 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.14 (bs,
1H), 8.0-7.98 (d, J = 7.2 Hz, 1H), 7.81-7.79 (d, J = 8.4 Hz, 2H),
7.07-7.05 (d, J = 8.4 Hz, 2H), 6.63-6.61 (d, J = 7.2 Hz, 1H), 6.19
(s, 1H), 3.81 (s, 3H), 2.32 (s, 3H). 6 ##STR00239## 373.06 98.08%,
Rt = 5.20 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.37
(bs, 1H), 8.07- 8.05 (d, J = 7.2 Hz, 1H), 8.02-8.0 (d, J = 8.8 Hz,
2H), 7.56-7.54 (d, J = 8.8 Hz, 2H), 6.68-6.66 (d, J = 7.2 Hz, 1H),
6.24 (s, 1H), 2.34 (s, 3H). 7 ##STR00240## 331.14 99.52%, Rt = 4.22
min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.37 (bs, 1H),
8.11- 8.09 (d, J = 8.4 Hz, 2H), 8.06-8.04 (d, J = 7.2 Hz, 1H),
8.01-7.99 (d, J = 8.4 Hz, 2H), 6.66-6.65 (d, J = 7.2 Hz, 1H), 6.24
(s, 1H), 2.66 (s, 3H), 2.34 (s, 3H). 8 ##STR00241## 367.06 98.98%,
Rt = 3.93 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.50
(bs, 1H), 8.14- 8.12 (m, 5H), 6.68-6.66 (d, J = 8.0 Hz, 1H), 6.25
(s, 1H), 3.27 (s, 3H), 2.34 (s, 3H). 9 ##STR00242## 384.11 98.41%,
Rt = 3.69 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.43
(bs, 1H), 8.77 (s, 1H), 8.64-8.63 (d, J = 4.4 Hz, 1H), 8.02-7.98
(m, 2H), 7.80- 7.74 (m. 3H), 7.55-7.51 (m, 1H), 6.59-6.58 (d, J = 6
Hz, 1H), 6.16 (s, 1H), 2.33 (s, 3H). 10 ##STR00243## 387.35 95.88%,
Rt = 1.44 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.34
(bs, 1H), 8.24- 8.23 (d, J = 2 Hz, 1H), 8.01- 8.0 (d, J = 6.8 Hz,
1H), 7.96 (s, 1H), 7.90-7.86 (m, 1H), 7.68-7.66 (d, J = 9.6 Hz,
2H), 6.61-6.60 (d, J = 6.8 Hz, 1H), 6.20 (s, 1H), 3.89 (s, 3H),
2.33 (s, 3H). 11 ##STR00244## 402.15 98.44%, Rt = 4.98 min (2)
.sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.44 (bs, 1H), 8.08- 8.06
(d, J = 6.8 Hz, 1H), 7.81-7.78 (d, J = 8.4 Hz, 1H), 7.67-7.63 (m,
1H), 6.73-6.71 (d, J = 7.2 Hz, 2H), 6.24 (s, 1H), 2.34 (s, 6H),
2.16 (s, 3H). 12 ##STR00245## 384.04 99.29%, Rt = 3.57 min (2)
.sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.44 (bs, 1H), 8.71- 8.69
(d, J = 5.6 Hz, 2H), 8.07-8.06 (d, J = 7.2 Hz, 1H), 7.83-7.80 (d, J
= 12 Hz, 3H), 6.62-6.61 (d, J = 4.4 Hz, 2H), 6.70-6.68 (d, J = 6.4
Hz, 1H), 6.24 (s, 1H), 2.34 (s, 3H). 13 ##STR00246## 366.06 97.71%,
Rt = 3.40 min (2) .sup.1HNMR (400 MHz, DMSO- d6 with D2O): .delta.
8.87 (s, 1H), 8.58-8.57 (d, J = 4.4 Hz, 1H), 8.11-8.09 (d, J = 7.6
Hz, 1H), 7.97-7.85 (m, 5H), 7.52-7.51 (d, J = 5.2 Hz, 1H), 6.55-
6.54 (d, J = 6.4 Hz, 1H), 6.15 (s, 1H), 2.31 (s, 3H). 14
##STR00247## 386.96 99.05%, Rt = 5.07 min (2) .sup.1HNMR (400 MHz,
DMSO- d6): .delta. 8.21 (bs, 1H), 7.85-7.83 (m, 2H), 7.76-7.74 (d,
J = 8.8 Hz, 1H), 7.64-7.58 (m, 1H), 6.33 (m, 1H), 6.06 (s, 1H),
2.31 (s, 3H). 15 ##STR00248## 369.15 99.67%, Rt = 4.19 min (2)
.sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.25 (bs, 1H), 8.25 (s,
1H), 8.02-8.0 (d, J = 7.2 Hz, 1H), 7.94 (s, 1H), 7.84-7.81 (d, J =
8.4 Hz, 2H), 7.73-7.71 (d, J = 8.4 Hz, 2H), 6.67-6.65 (d, J = 7.2
Hz, 1H), 6.21 (s, 1H), 3.86 (s, 3H), 2.33 (s, 3H). 16 ##STR00249##
384.17 99.81%, Rt = 4.75 min (2) .sup.1HNMR (400 MHz, DMSO- d6):
.delta. 13.39 (bs, 1H), 8.06- 8.04 (d, J = 7 Hz, 1H), 7.96- 7.94
(d, J = 8.4 Hz, 2H), 7.60-7.58 (d, J = 8.4 Hz, 2H), 6.73-6.72 (d, J
= 7 Hz, 1H), 6.23 (s, 1H), 2.43 (s, 3H), 2.33 (s, 3H), 2.25 (s,
3H). 17 ##STR00250## 356.09 95.76%, Rt = 3.63 min (2) .sup.1HNMR
(400 MHz, DMSO- d6): .delta. 13.33 (bs, 1H), 8.83 (s, 1H), 8.53 (s,
1H), 8.047-8.029 (d, J = 7.2 Hz, 1H), 7.98-7.92 (m, 4H), 6.67-6.65
(d, J = 7.2 Hz, 1H), 6.23 (s, 1H), 2.33 (s, 3H). 18 ##STR00251##
372.20 96.72%, Rt = 4.42 min (2) .sup.1HNMR (400 MHz, DMSO- d6):
.delta. 13.13 (bs, 1H), 7.96- 7.95 (d, J = 6.8 Hz, 1H), 7.63-7.61
(d, J = 8.4 Hz, 2H), 6.98-6.96 (d, J = 8.4 Hz, 2H), 6.62-6.60 (d, J
= 6.8 Hz, 1H), 6.17 (s, 1H), 3.24 (m, 4H), 2.32 (s, 3H), 1.56 (m,
6H). 19 ##STR00252## 358.16 97.95%, Rt = 5.03 min (2) .sup.1HNMR
(400 MHz, DMSO- d6): .delta. 7.89-7.88 (d, J = 6 Hz, 1H), 7.61-7.59
(d, J = 8 Hz, 2H), 6.56-6.52 (m, 3H), 6.11 (s, 1H), 3.25 (bs, 5H),
2.31 (s, 3H), 1.94 (s, 4H). 20 ##STR00253## 371.06 99.12%, Rt =
4.54 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 7.83-7.79 (t,
J = 6.8 Hz, 3H), 7.75-7.72 (d, J = 8.4 Hz, 2H), 7.61-7.58 (m, 2H),
7.16-7.14 (t, J = 4 Hz, 2H), 6.30-6.29 (d, J = 5.6 Hz, 1H), 6.01
(s, 1H), 2.30 (s, 3H). 21 ##STR00254## 373.05 98.86%, Rt = 4.47 min
(2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.45 (bs, 1H), 8.07-
8.06 (d, J = 6.8 Hz 1H), 7.93- 7.91 (d, J = 8 Hz, 1H), 7.78 (s,
1H), 7.72 (s, 1H), 7.65- 7.63 (d, J = 7.2 Hz, 1H), 6.67-6.5 (d, J =
7.2 Hz, 1H), 6.24 (s, 1H), 2.34 (s, 3H). 22 ##STR00255## 374.20
95.57%, Rt = 4.23 min (2) .sup.1HNMR (400 MHz, DMSO- d6 with
d-TFA): .delta. 7.97-7.95 (d, J = 7.6 Hz, 1H), 7.71-7.69 (d, J = 8
Hz, 2H), 7.02-6.99 (d, J = 8.8 Hz, 2H), 6.68-6.66 (d, J = 6.8 Hz,
1H), 6.17 (s, 1H), 3.71 (s, 4H), 3.21 (s, 4H), 2.31 (s, 3H). 23
##STR00256## 357.10 99.05%, Rt = 5.12 min (2) .sup.1HNMR (400 MHz,
DMSO- d6): .delta. 13.42 (bs, 1H), 8.10- 8.07 (m, 3H), 7.96-7.93
(d, J = 8.4 Hz, 2H), 6.67-6.66 (d, J = 7.2 Hz, 1H), 6.25 (s, 1H),
2.34 (s, 3H). 24 ##STR00257## 375.11 99.85%, Rt = 5.24 min (2)
.sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.46 (bs, 1H), 8.29- 8.26
(m, 1H), 8.16-8.15 (d, J = 6.4 Hz, 1H), 8.11-8.09 (d, J = 8 Hz,
1H), 7.76-7.72 (t, J = 9.6 Hz, 1H), 6.70-6.68 (d, J = 7.2 Hz, 1H),
6.26 (s, 1H), 2.34 (s, 3H). 25 ##STR00258## 357.06 97.77% Rt = 4.09
min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.40 (bs, 1H),
8.28- 8.27 (d, J = 7.6 Hz, 1H), 8.07-8.05 (d, J = 7.2 Hz, 1H),
7.96-7.94 (d, J = 7.6 Hz, 1H), 7.90-7.83 (m, 2H), 6.64-6.62 (d, J =
7.2 Hz, 1H), 6.25 (s, 1H), 2.32 (s, 3H). 26 ##STR00259## 355.18
98.77%, Rt = 4.45 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta.
13.34 (bs, 1H), 8.61- 8.60 (d, J = 2 Hz, 1H), 8.04- 8.02 (t, J =
7.6 Hz, 3H), 7.99- 7.97 (d, J = 9.2 Hz, 2H), 7.81 (s, 1H),
6.68-6.66 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 6.23 (s, 1H), 2.34 (s,
3H). 27 ##STR00260## 373.07 98.10%, Rt = 4.21 min (2) .sup.1HNMR
(400 MHz, DMSO- d6): .delta. 13.36 (bs, 1H), 8.08- 8.06 (m, 2H),
7.76-7.72 (m, 1H), 7.58-7.51 (m, 2H), 6.71- 6.69 (d, J = 6.8 Hz,
1H), 6.22 (s, 1H), 2.33 (s, 3H). 28 ##STR00261## 369.01 98.24%, Rt
= 4.13 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 7.95-7.94
(d, J = 6.6 Hz, 1H), 7.78-7.76 (d, J = 8.8 Hz, 2H), 7.73-7.71 (d, J
= 8.8 Hz, 2H), 6.48-6.47 (d, J = 6.6 Hz, 1H), 6.15 (s, 1H), 2.32
(s, 3H). 29 ##STR00262## 364.00 (M - 1) 99.24%, Rt = 3.61 min (2)
.sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.32 (bs, 1 H), 8.71- 8.69
(d, J = 6 Hz, 2H), 8.07- 7.97 (m, 5H), 7.80-7.78 (d, J = 6 Hz, 2H),
6.71-6.70 (d, J = 7.2 Hz, 1H), 6.24 (s, 1H), 2.34 (s, 3H). 30
##STR00263## 355.15 98.94%, Rt = 3.85 min (2) .sup.1HNMR (400 MHz,
DMSO- d6 with TFA): .delta. 8.22 (s, 2H), 8.01-7.99 (d, J = 7.2 Hz,
1H), 7.86-7.84 (d, J = 8.4 Hz, 2H), 7.78-7.76 (d, J = 8.4 Hz, 2H),
6.69-6.67 (d, J = 7.2 Hz, 1H), 6.20 (s, 1H), 2.32 (s, 3H). 31
##STR00264## 357.09 97.49%, Rt = 4.32 min (2) .sup.1HNMR (400 MHz,
DMSO- d6): .delta. 13.50 (bs, 1 H), 8.21- 8.19 (d, J = 7.6 Hz, 1H),
8.11 (s, 1H), 8.10-8.08 (d, J = 7.2 Hz, 1H), 8.03-8.01 (d, J = 7.6
Hz, 1H), 7.859-7.820 (t, J = 7.6 Hz, 1H), 6.711-6.693 (d, J = 7.2
Hz, 1H), 6.26 (s, 1H), 2.34 (s, 3H). 32 ##STR00265## 345.22 96.58%,
Rt = 4.96 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 8.01-7.99
(d, J = 6.8 Hz, 1H), 7.86 (s, 1H), 7.69- 7.67 (d, J = 7.6 Hz, 1H),
7.65-7.63 (d, J = 8.0 Hz, 1H), 7.50-7.46 (t, J = 7.8 Hz, 1H),
6.65-6.63 (d, J = 6.8 Hz, 1H), 6.18 (s, 1H), 2.31 (s, 3H), 1.30 (s,
9H). 33 ##STR00266## 352.97 (M - 1) 98.12%, Rt = 4.07 min (2)
.sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.38 (bs, 1 H), 8.05- 8.03
(d, J = 7.2 Hz, 1H), 7.94-7.92 (d, J = 8.4 Hz, 2H), 7.36 (s, 1H),
7.34-7.32 (d, J = 8.4 Hz, 2H), 6.66-6.64 (d, J = 7.2 Hz, 1H), 6.23
(s, 1H), 2.33 (s, 3H). 34 ##STR00267## 332.07 98.88%, Rt = 3.85 min
(2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 8.43-8.41 (m, 1H),
8.26-8.21 (m, 1H), 8.06-8.04 (d, .delta. 7 Hz, 1H), 7.71-7.67 (m,
1H), 6.64-6.62 (d, J = 7 Hz, 1H), 6.23 (s, 1H), 2.34 (s, 3H). 35
##STR00268## 348.10 99.12%, Rt = 4.84 min (2) .sup.1HNMR (400 MHz,
DMSO- d6): .delta. 13.48 (bs, 1 H), 8.41- 8.41 (d, J = 7.2 Hz, 1H),
8.16- 8.14 (d, J = 8.4 Hz, 1H), 8.06- 8.04 (d, J = 7.2 Hz, 1H),
7.93- 7.91 (d, J = 8.4 Hz, 1H), 6.63- 6.61 (d, J = 6.8 Hz, 1H),
6.24 (s, 1H), 2.34 (s, 3H). 36 ##STR00269## 307.09 98.48%, Rt =
4.36 min (2) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.31 (bs, 1
H), 8.05- 8.03 (d, J = 7 .2 Hz, 1H), 7.96- 7.92 (m, 2H), 7.41-7.37
(t, J = 8.0 Hz, 2H), 6.66-6.64 (d, J = 7.2 Hz, 1H), 6.23 (s, 1H),
2.33 (s, 3H).
Example 2
Synthesis of Compound 37
[4-(tert-butyl)-N-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)benzenesulf-
onamide] and Compounds 38-57
##STR00270##
[0255] Synthesis of VIII:
[0256] To a stirred solution of acetonitrile (2.3 g; 56 mmol) in
THF (20 mL) was added n-butyl lithium (35 mL; 56 mmol) dropwise at
-78.degree. C. under an argon atmosphere. The reaction mixture was
stirred for 30 minutes maintaining the same temperature. A solution
of cyclopropanecarbonyl chloride (VII; 3 g; 28 mmol) in THF (10 mL)
was added to the reaction mixture and the stirring continued for
1.5 hours at -50.degree. C. The reaction mixture was diluted with
IN hydrochloric acid and extracted sequentially with ethyl acetate
and dichloromethane (3.times.25 mL). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to afford
3-cyclopropyl-3-oxopropanenitrile as a crude solid (VIII; 3 g).
This was used in the next step without further purification.
[0257] Synthesis of IX:
[0258] A mixture of compound VIII (3 g; 27 mmol) and hydrazine
hydrate (2.25 mL; an excess) was dissolved in ethanol (150 mL) and
the reaction mixture heated at 80.degree. C. for 20 hours. The
reaction mixture was then cooled and concentrated under reduced
pressure. The crude product was purified by column chromatography
(2% MeOH-DCM) to obtain 3-cyclopropyl-1H-pyrazol-5-amine as a
yellow oil (IX; 1.5 g; 44% yield).
[0259] Synthesis of X:
[0260] To a stirred solution of 3-cyclopropyl-1H-pyrazol-5-amine
(IXx; 1.5 g; 12 mmol) in pyridine (20 mL) was added
3-(diethylamino)acrylonitrile (II; 2.4 g; 19 mmol). The reaction
mixture was heated at 120.degree. C. for 14 hours, whereupon it was
cooled and concentrated under reduced pressure. The crude mixture
was purified by column chromatography using 2% MeOH-DCM to obtain
2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine as a yellow solid (X;
1 g; 45% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 7.95-7.93
(d, J=5.2 Hz, 1H), 7.53 (bs, 2H), 6.02 (s, 1H), 5.97-5.95 (d, J=5.2
Hz, 1H), 2.07-2.0 (m, 1H), 0.98-0.96 (m, 2H), 0.82-0.81 (m, 2H). MS
(M+1): 175.03.
Synthesis of Compound 37:
4-(tert-butyl)-N-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfo-
namide
[0261] To a stirred solution of compound
2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (X; 200 mg; 1.14
mmol) in chloroform (10 mL) at 0.degree. C. was added pyridine (270
mg; 3.44 mmol) and 4-tertbutylsulfonyl chloride (XI; 400 mg; 1.72
mmol). The reaction mixture was heated at 80.degree. C. for 14
hours. The reaction mixture was cooled and concentrated at reduced
pressure to afford the di-substituted sulfonamide product (XII)
which was confirmed by LCMS. The crude product was further
dissolved in THF (4 mL) in presence of TBAF (0.2 mL) and stirred at
room temperature to 60.degree. C. for 3 hours. The reaction mixture
was concentrated, diluted with water and extracted with EtOAc
(3.times.25 mL). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to
afford the crude compound, which was purified by column
chromatography (4% MeOH-DCM) to afford the title compound
4-(tert-butyl)-N-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfo-
namide (37; 35 mg; 9% yield). .sup.1H NMR (400 MHz, DMSO-d6):
.delta. 13.23 (bs, 1H), 7.98-7.97 (d, J=7.0 Hz, 1H), 7.80-7.78 (d,
J=8.4 Hz, 2H), 7.57-7.55 (d, J=8.4 Hz, 2H), 6.65-6.63 (d, J=7.0 Hz,
1H), 6.06 (s, 1H), 2.07-2.0 (m, 1H), 1.28 (s, 9H), 1.01-0.96 (m,
2H), 0.82-0.78 (m, 2H). MS (M+1): 371.18. (LCMS purity 98.93%, 5.81
min) (2).
[0262] The Following Compounds were Prepared in Essentially the
Same Manner Using the Appropriate Sulfonyl Chloride in the Final
Step:
TABLE-US-00004 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
38 ##STR00271## 382.13 92.45%, Rt = 4.58 min (2) .sup.1H NMR (400
MHz, DMSO-d6): .delta. 13.33 (bs, 1H), 8.54 (s, 1H), 8.02-8.06 (d,
J = 7.2 Hz, 1H), 7.98-7.96 (dd, J = 8.4 Hz, 2H), 7.91-7.89 (dd, J =
8.4 Hz, 2H), 7.86 (s, 1H), 6.65-6.63 (d, J = 7.2 Hz, 1H), 6.10 (s,
1H), 2.07- 2.04 (m, 1H), 1.07-1.01 (m, 2H), 0.93-0.82 (m, 2H). 39
##STR00272## 383.06 99.16%, Rt = 4.52 min (2) .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 13.45 (bs, 1H), 8.21-8.19 (d, J = 7.6 Hz, 1H),
8.13 (s, 1H), 8.07-8.05 (d, J = 7.2 Hz, 1H), 8.03-8.01 (d, J = 7.2
Hz, 1H), 7.85-7.81 (t, J = 8.0 Hz, 1H), 6.68-6.66 (d, J = 7.2 Hz,
1H), 6.13 (s, 1H), 2.07-2.04 (m, 1H), 1.02-0.98 (m, 2H), 0.84-0.80
(m, 2H). 40 ##STR00273## 357.06 98.94%, Rt = 3.91 min (2) .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 13.38 (bs, 1H), 8.11-8.09 (d, J =
7.2 Hz, 2H), 8.02-7.99 (m, 3H), 6.64-6.62 (d, J = 7.6 Hz, 1H), 6.11
(s, 1H), 2.61 (s, 3H), 2.07-2.04 (m, 1H), 1.01-1.00 (m, 2H), 0.82
(m, 2H). 41 ##STR00274## 383.14 99.32%, Rt = 4.51 min (2) .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 8.07-8.05 (d, J = 8.0 Hz, 2H),
7.95-7.89 (m, 3H), 6.50-6.48 (d, J = 6.4 Hz, 1H), 6.05 (s, 1H),
2.04-2.01 (m, 1H), 0.99-0.97 (m, 2H), 0.80-0.79 (m, 2H). 42
##STR00275## 399.13 99.87%, Rt = 4.61 min (2) .sup.1H NMR (400 MHz,
DMSO-d6 with TFA): .delta. 8.02-7.99 (d, J = 8.8 Hz, 1H), 7.97-7.95
(d, J = 7.6 Hz, 2H), 7.45-7.43 (d, J = 7.6 Hz, 2H), 6.68-6.66 (d, J
= 7.2 Hz, 1H), 6.05 (s, 1H), 2.04- 2.03 (m, 1H), 0.98-0.96 (m, 2H),
0.80 (m, 2H). 43 ##STR00276## 345.10 98.77%, Rt = 4.03 min (2)
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 7.94-7.92 (d, J = 7.2 Hz,
1H), 7.80-7.77 (d, J = 8.8 Hz, 2H), 7.06-7.04 (d, J = 8.8 Hz, 2H),
6.56-6.54 (d, J = 6.8 Hz, 1H), 6.04 (s, 1H), 3.80 (s, 3H), 2.03 (m,
1H), 0.99-0.97 (m, 2H), 0.80-0.75 (m, 2H). 44 ##STR00277## 371.17
98.06%, Rt = 4.90 min (2) .sup.1H NMR (400 MHz, DMSO-d6): .delta.
13.20 (bs, 1H), 7.99-7.97 (d, J = 7.2 Hz, 1H), 7.87 (s, 1H),
7.69-7.67 (d, J = 7.6 Hz, 1H), 7.65-7.63 (d, J = 8.0 Hz, 1H),
7.50-7.46 (t, J = 7.8 Hz, 1H), 6.65-6.63 (d, J = 7.2 Hz, 1H), 6.07
(s, 1H), 2.04-2.01 (m, 1H), 1.30 (s, 9H), 0.99-0.96 (m, 2H),
0.82-0.78 (m, 2H). 45 ##STR00278## 383.09 99.61%, Rt = 4.35 min (2)
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.38 (bs, 1H), 8.28-8.26
(d, J = 7.6 Hz, 1H), 8.03-8.01 (d, J = 7.2 Hz, 1H), 7.96-7.94 (d, J
= 7.2 Hz, 1H), 7.89-7.80 (m, 2H), 6.60-6.58 (d, J = 7.2 Hz, 1H),
6.09 (s, 1H), 2.08-2.01 (m, 1H), 1.02-0.97 (m, 2H), 0.82- 0.80 (m,
2H). 46 ##STR00279## 401.10 99.79%, Rt = 4.75 min (2) .sup.1H NMR
(400 MHz, DMSO-d6): .delta. 13.52 (bs, 1H), 8.27-8.25 (m, 1H),
8.18-8.16 (d, J = 7.2 Hz, 1H), 8.07-8.05 (d, J = 7.2 Hz, 1H),
7.76-7.71 (t, J = 9.8 Hz, 2H), 6.67-6.65 (d, J = 7.2 Hz, 1H), 6.13
(s, 1H), 2.07-2.03 (m, 1H), 1.02-1.00 (m, 2H), 0.83 (m, 2H). 47
##STR00280## 329.13 98.66%, Rt = 4.17 min (2) .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 13.23 (bs, 1H), 7.98-7.96 (d, J = 7.2 Hz, 2H),
7.52-7.47 (m, 1H), 7.39-7.35 (m, 2H), 6.59- 6.57 (d, J = 7.6 Hz,
1H), 6.07 (s, 1H), 2.60 (s, 3H), 2.08-2.03 (m, 1H), 1.02-0.98 (m,
2H), 0.82- 0.80 (m, 2H). 48 ##STR00281## 399.16 96.01%, Rt = 4.88
min (2) .sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.36 (bs, 1H),
8.09-8.07 (d, J = 6.0 Hz, 1H), 8.04-8.02 (d, J = 7.2 Hz, 1H),
7.76-7.71 (m, 1H), 7.58-7.50 (m, 2H), 6.69-6.67 (d, J = 7.2 Hz,
1H), 6.12 (s, 1H), 2.05-2.03 (m, 1H), 1.02-0.97 (m, 2H), 0.83-0.79
(m, 2H). 49 ##STR00282## 393.17 98.11%, Rt = 4.05 min (2) .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 13.21 (bs, 1H), 8.12-8.07 (m, 4H),
8.00-7.99 (d, J = 6.4 Hz, 1H), 6.59-6.57 (d, J = 6.8 Hz, 1H), 6.08
(s, 1H), 3.20 (s, 3H), 2.04 (m, 1H), 1.00-0.98 (m, 2H), 0.81-0.80
(m, 2H). 50 ##STR00283## 399.15 97.60%, Rt = 5.01 min (2) .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 13.46 (bs, 1H), 8.06-8.04 (d, J =
7.2 Hz, 1H), 7.93-7.91 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.74-7.70
(t, J = 8.0 Hz, 1H), 7.65-7.63 (m, 1H) 6.66-6.64 (d, J = 7.2 Hz,
1H), 6.13 (s, 1H), 2.09-2.02 (m, 1H), 1.03-0.98 (m, 2H), 0.84-0.80
(m, 2H). 51 ##STR00284## 381.15 99.72%, Rt = 4.75 min (2) .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 13.31 (bs, 1H), 8.02-8.00 (d, J =
7.2 Hz, 1H), 7.94-7.92 (d, J = 8.8 Hz, 2H), 7.36-7.32 (m, 3H),
6.64-6.63 (d, J = 7.2 Hz, 1H), 6.10 (s, 1H), 2.07-2.01 (m, 1H),
1.01-0.99 (m, 2H), 0.83- 0.81 (m, 2H). 52 ##STR00285## 358.07
97.71%, Rt = 4.41 min (2) .sup.1H NMR (400 MHz, DMSO-d6): .delta.
13.41 (bs, 1H), 8.44-8.42 (m, 1H), 8.26-8.22 (m, 1H), 8.04- 8.02
(d, J = 7.2 Hz, 1H), 7.72- 7.67 (t, J = 9.0 Hz, 1H), 6.65- 6.63 (d,
J = 6.8 Hz, 1H), 6.12 (s, 1H), 2.07-2.02 (m, 1H), 1.03- 0.99 (m,
2H), 0.86-0.82 (m, 2H). 53 ##STR00286## 382.16 98.98%, Rt = 4.63
min (2) .sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.30 (bs, 1H),
8.77 (s, 1H), 8.52 (s, 1H), 8.00-7.92 (m, 5H), 6.65-6.63 (d, J =
7.2 Hz, 1H), 6.09 (s, 1H), 2.08-2.02 (m, 1H), 1.02-0.97 (m, 2H),
0.83-0.81 (m, 2H). 54 ##STR00287## 340.03 93.01%, Rt = 4.35 min (2)
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.41 (bs, 1H), 8.04 (m,
5H), 6.65-6.63 (d, J = 7.2 Hz, 1H), 6.13 (s, 1H), 2.09-2.02 (m,
1H), 1.03-0.98 (m, 2H), 0.84-0.80 (m, 2H). 55 ##STR00288## 387.25
98.42%, Rt = 4.98 min (2) .sup.1H NMR (400 MHz, DMSO-d6): .delta.
13.23 (bs, 1H), 7.98-7.96 (d, J = 7.2 Hz, 1H), 7.79-7.77 (d, J =
8.0 Hz, 2H), 7.38-7.36 (d, J = 8.4 Hz, 2H), 6.64-6.62 (d, J = 7.2
Hz, 1H), 6.07 (s, 1H), 3.29 (m, 2H), 3.22 (s, 3H), 2.68- 2.64 (m,
2H), 2.06-2.02 (m, 1H), 1.81-1.77 (m, 2H), 1.02-0.97 (m, 2H),
0.82-0.79 (m, 2H). 56 ##STR00289## 333.13 99.83%, Rt = 4.07 min (2)
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.31 (bs, 1H), 8.02-8.0
(d, J = 7.2 Hz, 1H), 7.96-7.92 (m, 2H), 7.41-7.37 (t, J = 8.8 Hz,
2H), 6.64-6.62 (d, J = 7.2 Hz, 1H), 6.10 (s, 1H), 2.05 (m, 1H),
1.01- 0.99 (m, 2H), 0.82-0.79 (m, 2H). 57 ##STR00290## 349.08
98.91%, Rt = 4.43 min (2) .sup.1H NMR (400 MHz, DMSO-d6): .delta.
13.35 (bs, 1H), 8.02-8.0 (d, J = 7.2 Hz, 1H), 7.89-7.87 (d, J = 8.8
Hz, 2H), 7.64-7.61 (d, J = 8.4 Hz, 2H), 6.62-6.60 (d, J = 7.2 Hz,
1H), 6.10 (s, 1H), 2.05 (m, 1H), 1.03-0.99 (m, 2H), 0.83-0.81 (m,
2H).
Example 3
Synthesis of Compound 58
[(4-(tert-butyl)-N-(6-cyanopyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfonami-
de] and Compounds 59-61
##STR00291##
[0264] Synthesis of XV:
[0265] A mixture of XIII (3 g; 36.14 mmol) and dimethylformamide
dimemethyl acetal (XIV; 4.3 g; 36.14 mmol) was heated to a reflux
in xylene (40 mL) for 3 hours. The reaction mixture was then
allowed to cool to room temperature and the product was collected
by filtration and crystallized from toluene to afford
N,N-dimethyl-N'-(1H-pyrazol-3-yl) formimidamide as a yellow solid
(XV; 3.8 g; 76% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta.
12.03 (bs, 1H), 7.94 (s, 1H), 5.77 (s, 1H), 2.98 (s, 3H), 2.88 (s,
3H).
[0266] Synthesis of XVI:
[0267] A mixture of XV (2.4 g; 17.39 mmol) and malononitrile (1.14
g; 17.39 mmol) was heated to a reflux in ethanol (20 mL) in the
presence of piperidine (2.9 g; 34 mmol) for 12 hours. The reaction
mixture was then allowed to cool to room temperature and the solid
product formed, was collected and crystallized to afford
7-aminopyrazolo[1,5-a]pyrimidine-6-carbonitrile (XVI; 1.9 g; 68%
yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.95 (bs, 2H), 8.32
(s, 1H), 8.24-8.23 (d, J=1.6, 1H), 6.59 (d, J=1.6, 1H). MS (M-1):
158.
[0268] Synthesis of Compound 58;
(4-(tert-butyl)-N-(6-cyanopyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfonamid-
e):
[0269] To a stirred solution
7-aminopyrazolo[1,5-a]pyrimidine-6-carbonitrile (XVI; 0.5 g; 3.14
mmol) in acetonitrile (10 mL) was added DIPEA (1.21 g; 9.43 mmol)
and 4-tertbutylphenylsulfonyl chloride (XI; 0.87 g; 3.77 mmol) at
0.degree. C. The reaction mixture was then heated at 90.degree. C.
for 12 hours. The reaction mixture was concentrated at reduced
pressure, diluted with cold water and extracted with
dichloromethane (3.times.20 mL). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum. The crude compound was purified through
a Combiflash.RTM. column using 3% MeOH-DCM as an eluent to afford
the title compound,
4-(tert-butyl)-N-(6-cyanopyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfonamide-
, as a white solid (58; 0.050 g, 4% yield). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 8.58 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.87-7.84
(d, J=8.4 Hz, 2H), 7.58-7.56 (d, J=8.4 Hz, 2H), 6.48 (d, J=2.0 Hz,
1H), 1.29 (s, 9H). MS (M+1): 356.09. (LCMS purity 97.26%, 4.87 min)
(1).
[0270] The Following Compounds were Prepared in Essentially the
Same Manner Using the Appropriate Sulfonyl Chloride in the Final
Step:
TABLE-US-00005 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
59 ##STR00292## 401.99 95.07%, Rt = 4.98 min (1) .sup.1H NMR (400
MHz, DMSO-d6): .delta. 8.50 (s, 1H), 8.36 (m, 1H), 8.20-8.18 (d, J
= 8.8 Hz, 1H), 8.10 (s, 1H), 7.93-7.90 (d, J = 8.4. Hz, 1H), 6.5
(s, 1H). 60 ##STR00293## 379.06 (M - 1) 98.28%, Rt = 3.77 min (1)
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.50 (s, 1H), 8.05 (s, 1H),
7.99-7.57 (m, 2H), 7.85-7.81 (m, 3H), 6.19 (s, 1H), 2.26 (s, 3H).
61 ##STR00294## 365.06 (M - 1) 98.95%, Rt = 3.55 min (1) .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 8.51 (s, 1H), 8.13 (s, 1H),
8.02-8.00 (m, 2H), 7.96-7.95 (d, J = 4 Hz, 1H), 7.86-7.84 (m, 2H),
7.82 (s, 1H) 6.40-6.4 (d, J = 2Hz, 1H).
Example 4
Synthesis of Compound 62
[4-(tert-butyl)-N-(2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)benzenes-
ulfonamide] and Compounds 63-74
##STR00295##
[0272] Synthesis of XVIII:
[0273] To a stirred solution of nicotinic acid (XVII; 10 g; 81
mmol) in methanol (90 mL) was added thionyl chloride (14.48 g; 122
mmol) drop wise at 0.degree. C. The reaction mixture was heated to
a reflux for 12 hours. The reaction mixture was cooled,
concentrated and diluted with water. The aqueous layer was
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were washed with sodium bicarbonate, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum to afford
methyl nicotinate as white solid (XVIII; 8 g, 75% yield). .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 9.08 (s, 1H), 8.23-8.80 (dd, J=1.2
Hz, 4.8 Hz, 1H), 8.30-8.827 (m, 1H), 7.58-7.55 (dd, J=5.0 Hz, 8 Hz,
1H), 3.88 (s, 3H). MS (M+1): 138.19.
[0274] Synthesis of XIX:
[0275] To a stirred solution of methyl nicotinate (XVIII; 8 g; 58
mmol) in toluene (110 mL) was added sodium hydride (2.8 g; 110
mmol) at 0.degree. C. The reaction mixture was stirred at 0.degree.
C. for 30 minutes and then acetonitrile (12 g; 91 mmol) was added.
The reaction mixture was heated to a reflux for 72 hours. The
reaction mixture was cooled, concentrated at reduced pressure and
diluted with ice cold water. The reaction mixture was acidified
using glacial acetic acid. The aqueous layer was extracted with
ethyl acetate (3.times.100 mL). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to afford
3-oxo-3-(pyridin-3-yl)propanenitrile as a yellow solid (XIX; 6 g,
70% yield). MS (M-1): 145.01.
[0276] Synthesis of XX:
[0277] To a stirred solution of
3-oxo-3-(pyridin-3-yl)propanenitrile (XIX; 5.8 g; 40 mmol) in
ethanol (190 mL) was added hydrazine hydrate (3.97 g; 80 mmol). The
reaction mixture was heated to a reflux for 12 hours. The reaction
mixture was cooled and concentrated to afford
3-(pyridin-3-yl)-1H-pyrazol-5-amine as a crude yellow solid (XX; 4
g, 63% yield). MS (M+1): 160.9.
[0278] Synthesis of XXI:
[0279] To a stirred solution of 3-(pyridin-3-yl)-1H-pyrazol-5-amine
(XX; 8 g; 50 mmol) in pyridine (80 mL) was added
3-(diethylamino)acrylonitrile (II; 9.3 g; 67 mmol). The reaction
mixture was heated at 100.degree. C. for 14 hours. The reaction
mixture was cooled and concentrated under reduced pressure. The
crude mixture was purified by column chromatography using 5%
MeOH-DCM to obtain 2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine
as a yellow solid (XXI; 1.8 g; 17% yield). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 9.26 (s, 1H), 8.60-8.59 (d, J=4.8 Hz, 1H),
8.39-8.37 (d, J=8 Hz, 1H), 8.08-8.07 (d, J=5.2 Hz, 1H), 7.78 (bs,
2H), 7.53-7.50 (m, 1H), 6.97 (s, 1H), 6.13-6.11 (d, J=5.2 Hz, 1H).
MS (M+1): 212.2.
Synthesis of Compound 62;
4-(tert-butyl)-N-(2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)benzenesu-
lfonamide
[0280] To a stirred solution of
2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (XXI; 0.4 g; 1.88
mmol) in acetonitrile (25 mL) was added triethylamine (0.62 g; 5.68
mmol) and 4-tertbutylphenylsulfonyl chloride (XI, 0.65 g; 2.84
mmol) at 0.degree. C. The reaction mixture was heated at 70.degree.
C. for 12 hours. The reaction mixture was concentrated at reduced
pressure and diluted with cold water and extracted with
dichloromethane (3.times.20 mL). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum. The crude compound was purified using
preparative HPLC to afford the title compound as a white solid (62;
0.025 g, 4% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.61
(bs, 1H), 9.20 (s, 1H), 8.64-8.63 (d, J=4.0 Hz, 1H), 8.40-8.38 (d,
J=7.2 Hz, 1H), 8.12-8.10 (d, J=8.4 Hz, 1H), 7.86-7.84 (m, 2H),
7.60-7.58 (m, 2H), 7.54-7.51 (m, 1H), 7.01 (s, 1H), 6.79-6.78 (m,
1H), 1.28 (s, 9H). MS (M+1): 408.14. (LCMS purity 96.89%, 4.78 min)
(1).
[0281] The Following Compounds were Prepared in Essentially the
Same Manner Using the Appropriate Sulfonyl Chloride in the Final
Step:
TABLE-US-00006 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
63 ##STR00296## 419.14 97.58%, Rt = 3.92 min (1) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 9.14 (bs, 1H), 8.58 (d, J = 3.2 Hz, 1H),
8.44 (s, 1H), 8.37-8.35 (d, J = 8 Hz, 1H), 8.0-7.97 (m, 3H),
7.88-7.86 (m, 2H), 7.77 (s, 1H), 7.54- 7.50 (m, 1H), 6.9 (s, 1H),
6.6-6.59 (d, J = 4, 1H). 64 ##STR00297## 420.07 98.34%, Rt = 4.93
min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 9.19 (s, 1H),
8.62-8.61 (d, J = 4 Hz, 1H), 8.39-8.37 (d, J = 8 Hz, 1H), 8.13-8.11
(d, J = 8 Hz, 2H), 8.08-8.06 (d, J = 8 Hz, 1H), 7.93-7.91 (d, J = 8
Hz, 2H), 7.53-7.49 (m, 1H), 6.98 (s, 1H), 6.63- 6.61 (d, J = 8 Hz,
1H). 65 ##STR00298## 436.12 97.53%, Rt = 4.68 min (1) .sup.1H NMR
(400 MHz, DMSO- d6 with D2O): .delta. 9.23 (s, 1H), 8.70-8.69 (d, J
= 4 Hz, 1H), 8.61-8.59 (d, J = 8 Hz, 1H), 8.13-8.11 (d, J = 7.2 Hz,
1H), 7.97-7.95 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.75- 7.70 (m,
2H), 7.63-7.61 (m, 1H), 7.05 (s, 1H) 6.80-6.79 (d, J = 6.8 Hz, 1H).
66 ##STR00299## 395.13 97.44%, Rt = 4.05 min (1) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 9.21 (s, 1H), 8.65-8.64 (d, J = 3.6 Hz,
1H), 8.50-8.48 (m, 1H), 8.41-8.39 (d, J = 8.4 Hz, 1H), 8.32-8.28
(m, 1H), 8.15-8.13 (m, 1H), 7.73-7.69 (m, 1H), 7.55-7.52 (m, 1H),
7.05 (s, 1H) 6.75-6.74 (d, J = 7.2, 1H). 67 ##STR00300## 438.13
99.57%, Rt = 4.72 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
11.94 (bs, 1H), 9.17 (s, 1H), 8.58-8.57 (d, J = 3.6 Hz, 1H),
8.36-8.34 (d, J = 7.6 Hz, 1H), 8.24-8.22 (m, 1H), 8.16-8.15 (d, J =
6.4 Hz, 1H), 7.98-7.97 (d, J = 5.6 Hz, 1H), 7.67-7.62 (t, J = 9.6
Hz, 1H), 7.50-7.47 (m, 1H), 6.89 (s, 1H) 6.44-6.43 (d, J = 5.6 Hz,
1H). 68 ##STR00301## 420.04 98.38%, Rt = 4.43 min (1) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 9.21 (s, 1H), 8.65-8.63 (m, 1H),
8.41-8.38 (m, 1H), 8.26-8.24 (d, J = 7.6 Hz, 1H), 8.19-8.15 (m,
2H), 8.03- 8.01 (d, J = 8.4 Hz, 1H), 7.86-7.82 (t, J = 8 Hz, 1H),
7.55-7.51 (m, 1H), 7.04 (s, 1H) 6.77-6.76 (d, J = 6.8 Hz, 1H). 69
##STR00302## 436.1 99.89%, Rt = 1.06 min (1) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 9.13 (s, 1H), 8.54-8.53 (d, J = 4.8 Hz, , 1H),
8.33- 8.31 (d, J = 8 Hz, 1H), 7.95- 7.93 (d, J = 8.8 Hz, 2H),
8.87-8.85 (d, J = 8 Hz, 1H), 7.47-7.42 (m, 3H), 6.79 (s, 1H),
6.33-6.31 (d, J = 5.6 Hz, 1H). 70 ##STR00303## 394.1 98.71%, Rt =
1.09 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 9.19 (s, 1H),
8.63-8.61 (d, J = 4.8 Hz, 1H), 8.39- 8.37 (d, J = 8 Hz, 1H), 8.1-
8.0 (m, 5H), 7.52-7.49 (m, 1H), 7.01 (s, 1H), 6.73-6.71 (d, J = 7.2
Hz, 1H). 2.65 (s, 3H). 71 ##STR00304## 366.06 97.02%, Rt = 4.14 min
(1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.65 (bs, 1H), 9.26
(s, 1H), 8.71-8.70 (d, J = 4.4 Hz, 1H), 8.55-8.53 (d, J = 8 Hz,
1H), 8.12-8.10 (d, J = 7.6 Hz, 1H), 7.82-7.80 (d, J = 8.4 Hz, 2H),
7.67-7.64 (m, 1H), 7.38-7.36 (d, J = 8 Hz, 2H), 7.05 (s, 1H),
6.76-6.74 (d, J = 7.2 Hz, 1H), 2.36 (s, 3H). 72 ##STR00305## 382.07
97.13%, Rt = 3.89 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
13.59 (bs, 1H), 9.24 (s, 1H), 8.68 (m, 1H), 8.49-8.47 (d, J = 8 Hz,
1H), 8.11-8.09 (d, J = 7.2 Hz, 1H), 7.87- 7.85 (d, J = 8.8 Hz, 2H),
7.62-7.58 (m, 1H), 7.10-7.08 (d, J = 8 Hz, 2H), 7.03 (s, 1H),
6.76-6.74 (d, J = 7.2 Hz, 1H), 3.81 (s, 3H). 73 ##STR00306## 430.08
97.91%, Rt = 3.64 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
9.23 (s, 1H), 8.66-8.64 (m, 1H), 8.41-8.39 (m, 1H), 8.18-8.09 (m,
5H), 7.54 (s, 1H), 7.02 (s, 1H), 6.72-6.70 (d, J = 6.8 Hz, 1H),
3.27 (s, 3H). 74 ##STR00307## 382.13 98.45%, Rt = 4.07 min (1)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 13.56 (bs, 1H), 9.27 (s,
1H), 8.70 (s, 1H), 8.55-8.53 (d, J = 8 Hz, 1H), 8.14-8.12 (d, J =
7.2 Hz, 1H), 7.66- 7.63 (m, 1H), 7.50-7.47 (m, 2H), 7.41 (s, 1H),
7.20-7.17 (m, 1H), 7.06 (s, 1H), 6.79- 6.77 (d, J = 7.2 Hz, 1H),
3.82 (s, 3H).
Example 5
Synthesis of Compound 75
[4-(tert-butyl)-N-(2-(4-cyanophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzene-
sulfonamide]
##STR00308##
[0283] Synthesis of XXIII:
[0284] To a stirred solution of 4-cyanobenzoic acid (XXII; 10 g; 68
mmol) in ethanol (150 mL) was added a catalytic quantity of
sulfuric acid (1 mL). The reaction mixture was heated to a reflux
for 12 hours. The reaction mixture was cooled, concentrated at
reduced pressure and diluted with water. The aqueous layer was
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were washed sequentially with sodium bicarbonate and brine,
then dried over Na.sub.2SO.sub.4, filtered and concentrated under
vacuum to afford ethyl 4-cyanobenzoate as a white solid (XXIII; 10
g, 84% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.10-8.08 (d,
J=8.4 Hz, 2H), 8.01-7.99 (d, J=8.4 Hz, 2H), 4.37-4.32 (q, J=7.2 Hz,
2H), 1.35-1.31 (t, J=7.2 Hz, 3H).
[0285] Synthesis of XXIV:
[0286] To a stirred solution of acetonitrile (1.4 g; 30 mmol) in
THF (30 mL) was added sodium hydride (2.28 g; 50 mmol) at 0.degree.
C. The stirring was continued for 30 minutes and then a solution of
ethyl 4-cyanobenzoate (XXIII; 5 g; 28 mmol) in THF (20 mL) was
added. The reaction mixture was stirred at 80.degree. C. for 12
hours. The reaction mixture was cooled, concentrated at reduced
pressure and diluted with ice cold water. The reaction mixture was
acidified using glacial acetic acid. The aqueous layer was
extracted with ethyl acetate (3.times.25 mL). The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum to afford
4-(2-cyanoacetyl)benzonitrile as a brown solid (XXIV; 1.5 g, 31%
yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.04-8.02 (d, J=8.4
Hz, 2H), 7.86-7.83 (d, J=8.4 Hz, 2H), 4.11 (s, 2H).
[0287] Synthesis of XXV:
[0288] To a stirred solution of 4-(2-cyanoacetyl)benzonitrile
(XXIV; 1.5 g; 8.8 mmol) in ethanol (30 mL) was added hydrazine
hydrate (1.32 g; 26 mmol). The reaction mixture was heated to a
reflux for 12 hours. The reaction mixture was cooled and
concentrated to afford 4-(5-amino-1H-pyrazol-3-yl)benzonitrile as a
crude off white solid (XXV; 0.6 g, 29% yield).
[0289] Synthesis of XXVI:
[0290] To a stirred solution of
4-(5-amino-1H-pyrazol-3-yl)benzonitrile (XXV; 1.7 g; 9.2 mmol) in
pyridine (15 mL) was added 3-(diethylamino)acrylonitrile (II; 1.7
g; 13.8 mmol). The reaction mixture was heated at 100.degree. C.
for 18 hours. The reaction mixture was cooled and concentrated
under reduced pressure. The crude mixture was purified by column
chromatography using 2% MeOH-DCM to obtain
4-(7-aminopyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile as an off
white solid (XXVI; 0.6 g; 27% yield). MS (M+1): 236.05.
Synthesis of Compound 75;
4-(tert-butyl)-N-(2-(4-cyanophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzenes-
ulfonamide
[0291] To a stirred solution of
4-(7-aminopyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (XXVI; 0.2 g;
0.85 mmol) in pyridine (5 mL) was added 4-tertbutylphenylsulfonyl
chloride (XI, 0.24 g; 1.02 mmol) and catalytic DMAP at 0.degree. C.
The reaction mixture was heated to a reflux for 12 hours. The
reaction mixture was concentrated under reduced pressure and the
purity improved using Combiflash.RTM. column chromatography and
further purified using preparative HPLC to afford the title
compound
4-(tert-butyl)-N-(2-(4-cyanophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzenes-
ulfonamide (75; 0.015 g, 4% yield) as white solid. .sup.1H NMR (400
MHz, DMSO-d6): .delta. 8.22-8.20 (d, J=8.4 Hz, 2H), 8.09-8.07 (d,
J=6.8 Hz, 1H), 7.95-7.93 (d, J=8.0 Hz, 2H), 7.85-7.83 (d, J=8.8 Hz,
2H), 7.59-7.56 (d, J=8.8 Hz, 2H), 7.01 (s, 1H), 6.75-6.73 (d, J=6.8
Hz, 1H), 1.28 (s, 9H). MS (M+1): 432.20. (LCMS purity 98.46%, 6.13
min) (2).
Example 6
Synthesis of Compound 76
[4-(tert-butyl)-N-(2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzene-
sulfonamide] and Compounds 77-78
##STR00309##
[0293] Synthesis of XXVIII:
[0294] To a stirred solution of 3-cyanobenzoic acid (XXVII; 6 g; 41
mmol) in methanol (80 mL) was added catalytic sulfuric acid (5 mL).
The reaction mixture was heated to a reflux for 12 hours. The
reaction mixture was cooled, concentrated under reduced pressure
and diluted with water. The aqueous layer was extracted with ethyl
acetate (3.times.50 mL). The combined organic layers were washed
with sodium bicarbonate, brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum to afford methyl
3-cyanobenzoate as a white solid (XXVIII; 3 g, 62% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 8.36 (s, 1H), 8.26-8.24 (d,
J=8.0 Hz, 1H), 7.84-7.82 (d, J=8.0 Hz, 1H), 7.63-7.58 (m 1H), 3.95
(s, 3H).
[0295] Synthesis of XXIX:
[0296] To a stirred solution of acetonitrile (3.8 g; 93 mmol) in
toluene (60 mL) was added sodium hydride (1.48 g; 38 mmol) at
0.degree. C. The stirring was continued for 30 minutes and then
methyl 3-cyanobenzoate (XXVIII; 3 g; 18 mmol) was added. The
reaction mixture was stirred at 100.degree. C. for 12 hours. The
reaction mixture was cooled and concentrated and diluted with ice
cold water. The reaction mixture was acidified using IN HCl. The
aqueous layer was extracted with ethyl acetate (3.times.25 mL). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum to afford
3-(2-cyanoacetyl)benzonitrile as a yellow solid (XXIX; 2.7 g, 18%
yield). MS (M-1): 169.10.
[0297] Synthesis of XXX:
[0298] To a stirred solution of 3-(2-cyanoacetyl)benzonitrile
(XXIX; 6 g; 35 mmol) in ethanol (80 mL) was added hydrazine hydrate
(15 mL). The reaction mixture was heated to a reflux for 12 hours.
The reaction mixture was cooled, concentrated at reduced pressure
and triturated with hexane to afford the title compound
3-(5-amino-1H-pyrazol-3-yl)benzonitrile as a crude sticky green
solid (XXX; 4 g, 71% yield). MS (M+1): 185.1.
[0299] Synthesis of XXXI:
[0300] To a stirred solution of
3-(5-amino-1H-pyrazol-3-yl)benzonitrile (XXX; 3 g; 17 mmol) in
pyridine (80 mL) was added 3-(diethylamino)acrylonitrile (II; 3.5
g; 29 mmol). The reaction mixture was heated at 100.degree. C. for
18 hours. The reaction mixture was cooled and concentrated under
reduced pressure. The crude mixture was purified by column
chromatography using 4% MeOH-DCM to afford
3-(7-aminopyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile as a light
brown solid (XXXI; 2.1 g; 58% yield). MS (M+1): 236.0.
Synthesis of Compound 76;
4-(tert-butyl)-N-(2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzenes-
ulfonamide
[0301] To a stirred solution of
3-(7-aminopyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (XXXI; 0.1 g;
0.43 mmol) in pyridine (3 mL) was added 4-tertbutylphenylsulfonyl
chloride (XI; 0.22 g; 94 mmol) and catalytic DMAP at 0.degree. C.
The reaction mixture was heated to a reflux for 36 hours. The
reaction mixture was concentrated at reduced pressure and purified
through Combiflash.RTM. column chromatography using 10% MeOH-DCM as
an eluent to afford
4-(tert-butyl)-N-(2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzenes-
ulfonamide as a white solid (76; 0.024 g, 12% yield). .sup.1H NMR
(400 MHz, DMSO-d6): .delta. 13.64 (bs, 1H), 8.46 (s, 1H), 8.38-8.36
(d, J=8 Hz, 1H), 8.12-8.10 (d, J=7.2 Hz, 1H), 7.91-7.84 (m, 3H),
7.72-7.68 (t, J=7.6 Hz, 1H), 7.60-7.58 (d, J=8 Hz, 2H), 7.05 (s,
1H), 6.70-6.79 (d, J=6.8 Hz, 1H), 1.29 (s, 9H). MS (M+1): 432.26.
(LCMS purity 97.29%, 6.09 min) (2).
[0302] The Following Compounds were Prepared in Essentially the
Same Manner Using the Appropriate Sulfonyl Chloride in the Final
Step:
TABLE-US-00007 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
77 ##STR00310## 444.17 95.76%, Rt = 5.81 min (2) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 8.47 (s, 1H), 8.39-8.37 (d, J = 8.4 Hz,
1H), 8.15-8.13 (m, 3H), 7.97-7.90 (m, 3H), 7.72-7.68 (m, 1H), 7.08
(s, 1H), 6.75-6.73 (d, J = 7.2 Hz, 1H). 78 ##STR00311## 443.27
97.85%, Rt = 5.0 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
8.50-8.48 (s, 1H), 8.41 (s, 1H) 8.37-8.35 (d, J = 8.0 Hz, 1H),
7.95-7.91 (m, 3H), 7.88- 7.79 (m, 5H), 7.69-7.65 (t, J = 7.6 Hz,
1H), 6.90 (s, 1H), 6.42-6.40 (d, J = 5.2 Hz, 1H).
Example 7
Synthesis of Compound 79
[4-(tert-butyl)-N-(2-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfon-
amide] and Compounds 80-84
##STR00312##
[0304] Synthesis of XXXIII:
[0305] To a stirred solution of 5-isopropyl-1H-pyrazol-3-amine
(XXXII; 1.5 g; 12 mmol) and 3-(diethylamino)acrylonitrile (II; 2.3
g; 18 mmol) in toluene (50 mL) was added acetic acid (16.5 mL). The
reaction mixture was heated at 140.degree. C. in a microwave for 10
minutes. The reaction mixture was cooled and concentrated under
reduced pressure. The crude mixture was purified by column
chromatography using 5% MeOH-DCM to obtain
2-isopropylpyrazolo[1,5-a]pyrimidin-7-amine as a light brown solid
(XXXIII; 1.2 g; 56% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta.
7.97-7.96 (d, J=5.2 Hz, 1H), 7.52 (bs, 2H), 6.18 (s, 1H), 5.98-5.97
(d, J=5.2 Hz, 1H), 3.09-3.02 (m, 1H), 1.30-1.28 (d, J=6.8 Hz, 6H).
MS (M+1): 177.0.
Synthesis of Compound 79;
4-(tert-butyl)-N-(2-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfona-
mide
[0306] To a stirred solution of
2-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (xxxiii; 0.25 g; 1.42
mmol) in chloroform (10 mL) was added pyridine (0.35 mL; 4.2 mmol)
and 4-tertbutylbenzenesulfonyl chloride (xi; 0.65 g; 2.1 mmol) at
0.degree. C. The reaction mixture was heated at 80.degree. C. for 6
hours. The reaction mixture was cooled and concentrated at reduced
pressure to afford the di-substituted sulfonamide product which was
confirmed by LCMS (XXXIV). The crude product was further dissolved
in THF in presence of TBAF and stirred at room temperature for 3
hours. The reaction mixture was concentrated and diluted with
water. The aqueous layer was extracted with EtOAc (3.times.25 mL).
The combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford the crude
compound, which was purified by column chromatography (5%
MeOH-DCM)) to obtain the title compound (79; 180 mg; 38% yield).
.sup.1HNMR (400 MHz, DMSO-d6): .delta. 13.30 (bs, 1H), 8.03-8.01
(d, J=7.6 Hz, 1H), 7.81-7.79 (d, J=8.4 Hz, 2H), 7.58-7.56 (d, J=8.4
Hz, 2H), 6.69-6.67 (d, J=7.2 Hz, 1H), 6.24 (s, 1H), 3.06-3.0 (m,
1H), 1.28 (s, 9H), 1.25-1.23 (d, J=6.8 Hz, 6H). MS (M+1): 373.24
LCMS purity 97.39%, 4.95 min (1).
[0307] The following compounds were prepared in essentially the
same manner using the appropriate sulfonyl chloride in the final
step.
TABLE-US-00008 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
80 ##STR00313## 419.12 95.91%, Rt = 5.98 min (1) .sup.1HNMR (400
MHz, DMSO- d6): .delta. 13.59 (bs, 1H), 8.22- 8.18 (m, 2H),
8.11-8.09 (d, J = 6.8 Hz, 1H), 7.96-7.94 (d, J = 8.4 Hz, 1H),
6.68-6.66 (d, J = 7.2 Hz, 1H), 6.30 (s, 1H), 3.07-3.03 (m, 1H),
1.26-1.25 (d, J = 6.8 Hz, 6H). 81 ##STR00314## 382.01 (M - 1)
98.47%, Rt = 4.03 min (1) .sup.1HNMR (400 MHz, DMSO- d6): .delta.
13.43 (bs, 1H), 8.53 (s, 1H), 8.05-8.03 (d, J = 7.2 Hz, 1H),
7.99-7.97 (d, J = 8.4 Hz, 2H), 7.91-7.89 (d, J = 8.4 Hz, 2H), 7.86
(s, 1H), 6.67-6.66 (d, J = 7.2 Hz, 1H), 6.27 (s, 1H), 3.06-3.02 (m,
1H), 1.26- 1.24 (d, J = 6.8 Hz, 6H). 82 ##STR00315## 401.15 99.61%,
Rt = 4.83 min (1) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.42
(bs, 1H), 8.07- 8.01 (m, 3H), 7.56-7.54 (d, J = 8.0 Hz, 2H),
6.67-6.65 (d, J = 7.2 Hz, 1H), 6.28 (s, 1H), 3.06-3.02 (m, 1H),
1.26-1.24 (d, J = 6.8 Hz, 6H). 83 ##STR00316## 335.11 99.12%, Rt =
4.24 min (1) .sup.1HNMR (400 MHz, DMSO- d6): .delta. 13.35 (bs,
1H), 8.04- 7.94 (m, 3H), 7.39 (m, 2H), 6.64 (m, 1H), 6.25 (s, 1H),
3.07-3.03 (m, 1H), 1.25-1.24 (s, 6H). 84 ##STR00317## 412.35 97.29%
Rt = 4.87 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 13.28
(bs, 1H), 8.01- 7.92 (m, 2H), 7.79-7.77 (d, J = 8 Hz, 2H),
7.45-7.42 (d, J = 13.6 Hz, 2H), 7.08 (s, 1H), 6.64-6.63 (d, J = 7.2
Hz, 1H), 6.23 (s, 1H), 3.07 (s, 5H), 1.25-1.24 (d, J = 6.8 Hz,
6H).
Example 8
Synthesis of Compound 85
[4-(tert-butyl)-N-(2-ethylpyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfonamid-
e] and Compounds 86-88
##STR00318##
[0309] Synthesis of XXXVI:
[0310] To a stirred solution of 3-oxopentanenitrile (XXXV; 2 g; 21
mmol) in ethanol (60 mL) was added hydrazine hydrate (1.3 mL; 41
mmol). The reaction mixture was heated to a reflux for 12 hours.
The reaction mixture was cooled and concentrated under reduced
pressure. The crude mixture was purified by column chromatography
using 8% MeOH-DCM to obtain 5-ethyl-1H-pyrazol-3-amine as a brown
sticky solid (XXXVI; 1.8 g; 78% yield). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 11.0 (bs, 1H), 5.17 (s, 1H), 4.5 (bs, 2H), 2.4
(m, 2H), 1.1 (m, 3H). MS (M+1): 111.93.
[0311] Synthesis of XXXVII:
[0312] To a stirred solution of 5-ethyl-1H-pyrazol-3-amine (XXXVI;
1.65 g; 15 mmol) and 3-(diethylamino)acrylonitrile (II; 2.76 g; 22
mmol) in toluene (22 mL) was added acetic acid (27 mL). The
reaction mixture was heated at 140.degree. C. in a microwave for 40
minutes. The reaction mixture was cooled and concentrated under
reduced pressure. The crude mixture was purified by column
chromatography using 6% MeOH-DCM to obtain
2-ethylpyrazolo[1,5-a]pyrimidin-7-amine as a sticky brown solid
(XXXVII; 1.7 g; 70% yield). .sup.1H NMR (400 MHz, DMSU-d6): .delta.
7.97-7.96 (d, J=5.2 Hz, 1H), 7.57 (bs, 2H), 6.18 (s, 1H), 5.99-5.98
(d, J=5.2 Hz, 1H), 2.77-2.71 (q, J=7.6 Hz, 2H), 1.28-1.24 (t, J=7.6
Hz, 3H). MS (M+1): 162.96.
Synthesis of Compound 85;
4-(tert-butyl)-N-(2-ethylpyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfonamide
[0313] To a stirred solution of compound
2-ethylpyrazolo[1,5-a]pyrimidin-7-amine (XXXVII; 0.20 g; 1.23 mmol)
in chloroform (10 mL) was added pyridine (0.3 mL; 3.7 mmol) and
4-tertbutylbenzenesulfonyl chloride (XI; 0.57 g; 2.4 mmol) at
0.degree. C. The reaction mixture was heated at 80.degree. C. for
10 hours, whereupon it was allowed to cool and was concentrated at
reduced pressure. The reaction mixture was diluted with water and
the aqueous layer was extracted with EtOAc (3.times.25 mL). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford the crude
compound, which was purified by column chromatography (5% MeOH-DCM)
to obtain the title compound
4-(tert-butyl)-N-(2-ethylpyrazolo[1,5-a]pyrimidin-7-yl)benzenesulfonamide
(85; 60 mg; 14% yield). .sup.1HNMR (400 MHz, DMSO-d6): .delta.
13.32 (bs, 1H), 8.03-8.01 (d, J=7.2 Hz, 1H), 7.81-7.79 (d, J=8.4
Hz, 2H), 7.58-7.56 (d, J=8.4 Hz, 2H), 6.70-6.68 (d, J=7.2 Hz, 1H),
6.24 (s, 1H), 2.72-2.66 (q, J=7.6 Hz, 2H), 1.28 (s, 9H), 1.23-1.19
(t, J=7.6 Hz, 3H). MS (M+1): 359.22. (LCMS purity 99.46%, 5.24 min)
(2).
[0314] The Following Compounds were Prepared in Essentially the
Same Manner Using the Appropriate Sulfonyl Chloride in the Final
Step:
TABLE-US-00009 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
86 ##STR00319## 370.09 98.62%, Rt = 3.75 min (2) .sup.1HNMR (400
MHz, DMSO-d6): .delta. 13.41 (bs, 1H), 8.53 (s, 1H), 8.03-8.01 (d,
J = 6.8 Hz, 1H), 7.97-7.95 (d, J = 8.4 Hz, 2H), 7.90-7.88 (m, 2H),
7.85 (s, 1H), 6.63-6.61 (d, J = 6.8, 1H), 6.24 (s, 1H), 2.73-2.67
(q, J = 7.6 Hz, 2H), 1.24-1.20 (t, J = 7.6 Hz, 3H). 87 ##STR00320##
405.14 99.53%, Rt = 5.74 min (2) .sup.1HNMR (400 MHz, DMSO-d6):
.delta. 13.62 (bs, 1H), 8.19-8.17 (m, 2H), 8.12-8.10 (d, J = 7.2
Hz, 1H), 7.96-7.94 (d, J = 8 Hz, 1H), 6.69-6.67 (d, J = 7.2 Hz,
1H), 6.30 (s, 1H), 2.74-2.68 (q, J = 7.4 Hz, 2H), 1.24-1.21 (t, J =
7.4 Hz, 3H). 88 ##STR00321## 321.08 99.32%, Rt = 3.98 min (2)
.sup.1HNMR (400 MHz, DMSO-d6): .delta. 13.34 (bs, 1H), 8.05-8.04
(d, J = 7.2 Hz, 1H), 7.96-7.93 (m, 2H), 7.41-7.37 (m, 2H), 6.67-
6.65 (d, J = 7.2 Hz, 1H), 6.26 (s, 1H), 2.73-2.67 (q, J = 7.6 Hz,
2H), 1.24-1.21 (t, J = 7.6 Hz, 3H).
Example 9
Synthesis of Compound 89
[4-(tert-butyl)-N-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzen-
esulfonamide] and Compound 90
##STR00322##
[0316] Synthesis of XXXIX:
[0317] To a stirred solution of 4-chlorobenzoic acid (XXXVIII; 15
g; 9.61 mmol) in ethanol (150 mL) was added a catalytic quantity of
sulfuric acid (3 mL). The reaction mixture was heated to a reflux
for 12 hours, whereupon it was cooled, concentrated under reduced
pressure and diluted with water. The aqueous layer was extracted
with ethyl acetate (3.times.60 mL). The combined organic layers
were washed with successively with sodium bicarbonate and brine,
followed by drying over Na.sub.2SO.sub.4, filtration and
concentration under vacuum to afford ethyl 4-chlorobenzoate as a
white solid (XXXIX; 12 g, 71% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.96-7.94 (d, J=8.4 Hz, 2H), 7.60-7.58 (d,
J=8.4 Hz, 2H), 4.33-4.28 (q, J=7.2 Hz, 2H), 1.33-1.29 (t, J=7.2 Hz,
3H).
[0318] Synthesis of XL:
[0319] To a stirred solution of acetonitrile (10 mL) in toluene
(100 mL) was added sodium hydride (3.26 g; 81 mmol) at 0.degree. C.
The stirring was continued for 30 minutes and then ethyl
4-chlorobenzoate (XXXIX; 5 g; 27 mmol) was added. The reaction
mixture was stirred at 100.degree. C. for 12 hours. The reaction
mixture was cooled, concentrated at reduced pressure and diluted
with ice cold water. The reaction mixture was acidified using IN
hydrochloric acid. The aqueous layer was extracted with ethyl
acetate (3.times.25 mL). The combined organic layers were washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under vacuum to afford the title compound
3-(4-chlorophenyl)-3-oxopropanenitrile as a crude light yellow
solid (XL; 3 g, 61% yield).
[0320] Synthesis of XLI:
[0321] To a stirred solution of
3-(4-chlorophenyl)-3-oxopropanenitrile (XL; 1.5 g; 8.3 mmol) in
ethanol (75 mL) was added hydrazine hydrate (0.8 g; 16.7 mmol). The
reaction mixture was heated to a reflux for 12 hours. The reaction
mixture was cooled and concentrated under reduced pressure and then
diluted with water. The aqueous layer was extracted using ethyl
acetate (3.times.20 mL) and triturated with hexane to afford
3-(4-chlorophenyl)-1H-pyrazol-5-amine as a yellow solid (XLI; 1 g,
60% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 11.81 (bs,
1H), 7.67-7.65 (d, J=8.4 Hz, 2H), 7.42-7.40 (d, J=8.4 Hz, 2H), 5.74
(s, 1H), 4.85 (bs, 2H). MS (M-1): 192.27.
[0322] Synthesis of XLII:
[0323] To a stirred solution of
3-(4-chlorophenyl)-1H-pyrazol-5-amine (XLI; 0.6 g; 3.1 mmol) in
piperidine (0.53 g; 4.6 mmol) was added
3-(diethylamino)acrylonitrile (II; 0.58 g; 4.6 mmol). The reaction
mixture was heated at 100.degree. C. for 18 hours. On cooling,
solvent was removed under reduced pressure. The crude mixture was
triturated with hexane to afford
2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-amine as an off-white
solid (XLII; 0.5 g; 65% yield). .sup.1H NMR (400 MHz, DMSO-d6):
.delta. 8.08-8.05 (m, 3H), 7.75 (bs, 2H), 7.56-7.51 (d, J=8.4 Hz,
2H), 6.89 (s, 1H), 6.1-6.09 (m, 1H).
Synthesis of Compound 89;
4-(tert-butyl)-N-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzene-
sulfonamide
[0324] To a stirred solution of
2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-amine (XLII 0.1 g;
0.41 mmol) in pyridine (5 mL) was added
4-tertbutylphenylsulfonylchloride (XI 0.12 g; 0.49 mmol) and
catalytic DMAP at 0.degree. C. The reaction mixture was heated to a
retlux tor 24 hours. On cooling, the reaction mixture was
concentrated and purified using Combiflash.RTM. column
chromatography and 3% MeOH-DCM as an eluent to afford the title
compound
4-(tert-butyl)-N-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)benzene-
sulfonamide as a white solid (89; 0.024 g, 12% yield). .sup.1H NMR
(400 MHz, DMSO-d6): .delta. 13.53 (bs, 1H), 8.09-8.03 (m, 3H),
7.85-7.83 (d, J=8 Hz, 2H), 7.59-7.52 (m, 4H), 6.91 (s, 1H),
6.78-6.77 (m, 1H), 1.29 (s, 9H). MS (M+1): 441.10. (LCMS purity
96.19%, 5.23 min) (1).
[0325] The Following Compound was Prepared in Essentially the Same
Manner Using the Appropriate Sulfonyl Chloride in the Final
Step:
TABLE-US-00010 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
90 ##STR00323## 452.05 95.05%, Rt = 5.51 min (2) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 13.62 (bs, 1H), 8.53 (s, 1H), 8.10-8.0 (m,
5H), 7.92- 7.90 (d, J = 8.4 Hz, 2H), 7.86 (s, 1H), 7.55-7.53 (d, J
= 8.4 Hz, 2H), 6.92 (s, 1H), 6.73-6.71 (d, J = 7.2 Hz, 1H).
Example 10
Synthesis of Compound 91
[N-(2-(1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4-(tert-butyl)benz-
enesulfonamide]
##STR00324## ##STR00325##
[0327] Synthesis of XLIV:
[0328] To a stirred solution of 1H-imidazole-4-carboxylic acid
(XLIII; 5 g; 44.64 mmol) in ethanol (100 ml) was added sulfuric
acid (3 ml). The reaction mixture was heated at 80.degree. C. for
12 h. The reaction mixture was cooled, concentrated at reduced
pressure and diluted with water. The aqueous layer was extracted
with ethyl acetate. The combined organic layers were washed with
sodium bicarbonate and brine solution, dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum to afford ethyl
imidazole-4-carboxylate as a white solid (XLIV, 4.75 g, 76% yield).
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.75 (bs, 1H), 7.77 (s,
2H), 4.24-4.19 (q, J=7.2 Hz, 2H), 1.28-1.24 (t, J=6.8 Hz, 3H). MS
(M+1) 141.12.
[0329] Synthesis of XLV:
[0330] To a stirred solution of XLIV, (2 g; 14 mmol) in
dimethylformide (50 ml) was added trityl chloride (3.98 g; 14 mmol)
and triethylamine (1.73 g, 17 mmol) at 0.degree. C. The resulting
solution was stirred for 12 h at room temperature. The reaction
mixture was cooled, concentrated at reduced pressure and diluted
with water. The aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum to afford
ethyl 1-trityl-1H-imidazole-4-carboxylate as a brown solid (XLV; 3
g, 55% yield). MS (M+1) 383.34.
[0331] Synthesis of XLVI:
[0332] To a stirred solution of acetonitrile (0.32 g; 7.80 mmol) in
tetrahydrofuran (20 ml) was added sodium bis(trimethylsilyl)amide
(15.7 ml, 1.0M in THF, 15.69 mmol at 0.degree. C. The stirring was
continued for 30 minutes and then a solution of ethyl
1-trityl-1H-imidazole-4-carboxylate (XLV; 2 g; 5.23 mmol) in THF
(20 ml) was added. The reaction mixture was stirred at 80.degree.
C. for 12 h. The reaction mixture was cooled, concentrated at
reduced pressure and diluted with ice cold water. The aqueous layer
was extracted with ethyl acetate, and the resulting organic layer
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to afford
3-oxo-3-(1-trityl-1H-imidazol-4-yl)propanenitrile as a brown solid
(XLVI; 1 g, 50% yield). MS (M+1) 378.34.
[0333] Synthesis of XLVII:
[0334] To a stirred solution of compound XLVI (1 g; 2.65 mmol) in
ethanol (10 ml) was added hydrazine hydrate (10 ml). The reaction
mixture was heated at 90.degree. C. for 12 h and then cooled and
concentrated to afford
3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazol-5-amine as a crude
yellowish solid (XLVII; 0.6 g, 57% yield). MS (M+1) 392.12. The
crude material was carried forward to the next step without
purification.
[0335] Synthesis of XLVIII:
[0336] To a stirred solution of compound XLVII (1 g; 2.55 mmol) in
pyridine (30 ml) was added 3-(diethylamino)acrylonitrile II (0.47
g; 3.82 mmol). The reaction mixture was heated at 100.degree. C.
for 18 h. The reaction mixture was cooled and concentrated under
reduced pressure. The crude mixture was purified by column
chromatography using 2% methanol in dichloromethane to obtain
2-(1-trityl-1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine as a
yellowish solid (XLVIII; 0.6 g; 54% yield). MS (M+1): 443.12.
[0337] Synthesis of XLIX:
[0338] To a stirred solution of compound XLVIII (0.5 g; 1.12 mmol)
in pyridine (10 ml) was added 4-tert-butylphenylsulfonyl chloride
(XI; 0.47 g; 2.03 mmol) and catalytic DMAP. The reaction mixture
was heated at 100.degree. C. for 12 h and then concentrated under
reduced pressure and purified by column chromatography using 25%
ethyl acetate in hexane to afford XLIX (0.3 g, 41% yield) as a
yellowish solid. MS (M-1): 637.20.
Synthesis of Compound 91:
N-(2-(1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4-(tert-butyl)benze-
nesulfonamide
[0339] To a stirred solution of XLIX (0.3 g; 0.47 mmol) in water (4
ml) at 0.degree. C. was added trifluoroacetic acid (6 ml). The
reaction mixture was stirred at room temperature for 12 h whereupon
it was concentrated under reduced pressure and purified by column
chromatography using 5% methanol in dichloromethane to afford the
title compound (91; 0.022 g, 12% yield) as a white solid. .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 13.06 (bs, 1H), 8.03 (s, 1H),
7.95-7.93 (d, J=6.4 Hz, 1H), 7.79-7.74 (m, 3H), 7.53-7.51 (d, J=8.4
Hz, 2H), 6.56 (s, 1H), 6.54-6.53 (d, J=6.8 Hz, 1H), 1.27 (s, 9H).
MS (M+1): 397.21. (LCMS purity 99.38%, Rt=4.78 min) (2).
Example 11
Synthesis of Compound 92
[4-(tert-butyl)-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-
-yl)benzenesulfonamide]
##STR00326##
[0341] Synthesis of LI:
[0342] To a stirred solution of ethyl 1H-pyrazole-4-carboxylate (L,
4 g; 28.5 mmol) in tetrahydrofuran (50 ml) was added sodium hydride
(1.36 g, 28.5 mmol) at 0.degree. C. The reaction mixture was
stirred for 1 h. Methyl iodide (6.07 g, 42.8 mmol) was added and
the reaction was stirred for 18 h at room temperature. The reaction
mixture was concentrated under reduced pressure and diluted with
water. The resulting aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with sodium
bicarbonate, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to afford ethyl
1-methyl-1H-pyrazole-4-carboxylate as a yellow liquid (LI; 3.5 g,
77% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.88 (s,
1H), 7.85 (s, 1H), 4.31-4.25 (q, J=7.2 Hz, 2H), 3.9 (s, 3H),
1.35-1.31 (t, J=7.2 Hz, 3H). MS (M+1) 155.12.
[0343] Synthesis of LII:
[0344] To a stirred solution of acetonitrile (1.3 g; 34 mmol) and
ethyl 1-methyl-1H-pyrazole-4-carboxylate (LI; 3.5 g, 22.72 mmol) in
THF (20 ml) was added sodium bis(trimethylsilyl)amide (68.18 ml,
1.0 M in THF, 68.18 mmol) at -78.degree. C. The stirring was
continued for 2 h at the same temperature whereupon the reaction
mixture was allowed to warm to room temperature, concentrated at
reduced pressure and diluted with water. The aqueous layer was
extracted with ethyl acetate, which was subsequently washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
vacuum to afford 3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile
as a yellowish solid (LII; 2.5 g, 69% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.01 (s, 1H), 7.94 (s, 1H), 3.97 (s, 3H), 3.79
(s, 2H). MS (M+1) 150.12.
[0345] Synthesis of LIII:
[0346] To a stirred solution of
3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile (LII; 2.5 g; 16.7
mmol) in ethanol (100 ml) was added hydrazine hydrate (1.67 g, 33.5
mmol). The reaction mixture was heated at 90.degree. C. for 24 h,
cooled, concentrated at reduced pressure and triturated with hexane
to afford LIII as an off white solid (1.6 g, 59% yield). .sup.1H
NMR (400 MHz, DMSO d6): .delta. 11.49 (bs, 1H), 7.86 (s, 1H), 7.62
(s, 1H), 5.48 (s, 1H), 4.6 (bs, 2H), 3.82 (s, 3H). MS (M+1):
164.1.
[0347] Synthesis of LIV:
[0348] To a stirred solution of LIII (0.25 g; 1.53 mmol) in acetic
acid (6 ml) was added 3-(diethylamino)acrylonitrile (II; 0.28 g;
2.3 mmol). The reaction mixture was heated at 80.degree. C. for 20
minutes in a microwave reactor. The reaction mixture was cooled and
concentrated under reduced pressure. The crude mixture was
triturated with dichloromethane to afford LIV (0.1 g; 76% yield).
.sup.1H NMR (400 MHz, DMSO d6): .delta. 8.46 (bs, 2H), 8.22 (s,
1H), 8.11-8.09 (d, J=5.6 Hz, 1H), 7.93 (s, 1H), 6.62 (s, 1H),
6.15-6.14 (d, J=5.6 Hz, 1H), 3.91 (s, 3H). MS (M+1): 215.0.
Synthesis of Compound 92;
4-(tert-butyl)-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7--
yl)benzenesulfonamide
[0349] To a stirred solution of LIV (0.2 g; 0.93 mmol) in
chloroform (30 ml) at 0.degree. C. was added pyridine (0.3 ml) and
4-tert-butylbenzenesulfonyl chloride (XI; 0.26 g; 1.11 mmol). The
reaction mixture was heated to 100.degree. C. for 42 h, then cooled
and concentrated at reduced pressure. The crude mixture was
purified by column chromatography using 2% methanol in
dichloromethane to afford the title compound as an off white solid
(92; 0.025 g, 7% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta.
13.36 (bs, 1H), 8.32 (s, 1H), 8.03-8.01 (d, J=7.6 Hz, 1H), 7.94 (s,
1H), 7.83-7.81 (d, J=8.4 Hz, 2H), 7.58-7.56 (d, J=8.0 Hz, 2H),
6.71-6.70 (d, J=7.8 Hz, 1H), 6.58 (s, 1H), 3.87 (s, 3H), 1.28 (s,
9H). MS (M+1): 411.19. (LCMS purity 98.22%, Rt=5.32 min) (2).
Example 12
Synthesis of Compound 93
[4-(tert-butyl)-N-(2-(5-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-
benzenesulfonamide]
##STR00327##
[0351] Synthesis of LVI:
[0352] To a stirred solution of 5-chloronicotinic acid (LV, 5 g;
31.8 mmol) in methanol (40 ml) was added sulfuric acid (4 ml). The
reaction mixture was heated at 75.degree. C. for 12 h. The reaction
mixture was cooled, concentrated under reduced pressure and diluted
with water. The aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with sodium bicarbonate, brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum
to afford methyl 5-chloronicotinate as a white solid (LVI; 4.4 g,
80% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.08 (d,
J=1.6 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.28-8.27 (t, J=2.0 Hz, 1H),
3.96 (s, 3H). MS (M+1): 172.12
[0353] Synthesis of LVII:
[0354] To a stirred solution of acetonitrile (0.95 g; 23 mmol) in
tetrahydrofuran (30 ml) was added potassium tert butoxide (0.19 g;
23 mmol) at 0.degree. C. The stirring was continued for 30 minutes
and then 5-chloronicotinate (LVI; 2.58 g; 19.23 mmol) was added.
The reaction mixture was stirred at room temperature for 3 h. The
reaction mixture was concentrated and diluted with ice cold water.
The aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum to afford
3-(5-chloropyridin-3-yl)-3-oxopropanenitrile as a red sticky solid
(LVII; 2.7 g). MS (M+1): 181.12.
[0355] Synthesis of LVIII:
[0356] To a stirred solution of
3-(5-chloropyridin-3-yl)-3-oxopropanenitrile (LVII; 2.7 g; 14.9
mmol) in ethanol (15 ml) was added hydrazine hydrate (0.82 g, 16.39
mmol). The reaction mixture was heated at 100.degree. C. for 12 h.
The reaction mixture was cooled, concentrated at reduced pressure
and triturated with hexane to afford the title compound
3-(5-chloropyridin-3-yl)-1H-pyrazol-5-amine as an off white solid
(LVIII; 1.4 g) MS (M+1): 195.1.
[0357] Synthesis of LIX:
[0358] To a stirred solution of
3-(5-chloropyridin-3-yl)-1H-pyrazol-5-amine (LVIII; 1.45 g; 7.43
mmol) in acetic acid (60 ml) was added
3-(diethylamino)acrylonitrile (II; 1.10 g; 8.9 mmol). The reaction
mixture was heated at 100.degree. C. for 18 h. The reaction mixture
was cooled and concentrated under reduced pressure. The crude
mixture was purified by column chromatography using 4% methanol in
dichloromethane to afford
2-(5-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as a light
brown solid (LIX; 0.9 g; 49% yield). MS (M+1): 246.0.
Synthesis of Compound 93;
4-(tert-butyl)-N-(2-(5-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)b-
enzenesulfonamide
[0359] To a stirred solution of
2-(5-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (LVIX; 0.2
g; 0.81 mmol) in pyridine (3 ml), 4-(tert-butyl)benzenesulfonyl
chloride (XI; 0.22 g; 0.97 mmol) and a catalytic quaniy of DMAP
were added. The reaction mixture was heated to 90.degree. C. for 12
h. The reaction mixture was cooled and concentrated at reduced
pressure. The crude mixture was purified by column chromatography
using 3% methanol in dichloromethane to afford the title product,
4-(tert-butyl)-N-(2-(5-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)b-
enzenesulfonamide as an off white solid (93; 0.05 g, 16% yield).
.sup.1H NMR (400 MHz, DMSO-d6): .delta.13.6 (bs, 1H), 9.17 (d,
J=2.0 Hz, 1H), 8.70-8.69 (d, J=2.4 Hz, 1H), 8.49-8.48 (d, J=2.0 Hz,
1H), 8.13-8.11 (d, J=7.2 Hz, 1H), 7.86-7.84 (d, J=8.4 Hz, 2H),
7.60-7.58 (d, J=8.4 Hz, 2H), 7.10 (s, 1H), 6.82-6.80 (d, J=7.8 Hz,
1H), 1.29 (s, 9H). MS (M+1): 442.30. (LCMS purity 95.12%, Rt=6.43
min) (2).
Example 13
Synthesis of Compound 94
[4-(tert-butyl)-N-(4-chloro-2-methylpyrazolo[1,5-a]pyridin-7-yl)benzenesu-
lfonamide]; Compound 95
[4-(tert-butyl)-N-(4-cyano-2-methylpyrazolo[1,5-a]pyridin-7-yl)benzene
sulfonamide]; and Compounds 96-109
##STR00328## ##STR00329##
[0361] Synthesis of LXI:
[0362] To a stirred solution of 2-Mesitylenesulfonyl chloride (LX;
20 g, 91.45 mmol) in methyl tert-butyl ether (200 ml) was added
tert-butyl N-hydroxycabamate (12.17 g, 91.45 mmol). The reaction
mixture was purged with nitrogen and cooled to 0.degree. C.
Triethylamine (8.43 g, 93.27 mmol) was added dropwise with stirring
at 0.degree. C. The resultant mixture was stirred for a further 2
h. The reaction mixture was filtered to remove triethylamine
hydrochloride and washed with methyl tert-butyl ether. The liquid
phase was concentrated at 20.degree. C. to a minimum volume and
triturated with n-hexane. The solid so obtained was filtered and
dried to afford, tert-butyl ((mesitylsulfonyl)oxy)carbamate as a
white solid. (LXI; 23 g, 79% yield). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 11.15 (bs, 1H), 7.13 (s, 2H), 2.56 (s, 6H), 2.29
(s, 3H), 1.24 (s, 9H). MS (M+1): 316.15.
[0363] Synthesis of LXII:
[0364] To a stirred solution of trifluroacetic acid (30 ml) at
0.degree. C. was added LXI (10 g, 31.70 mmol) in portionwise
fashion. The reaction mixture was stirred at 0.degree. C. for 2 h,
whereupon it was diluted with crushed ice with cold water. A white
solid precipitated, which was isolated by filtration, washed with
ice cold water until the washings reached a neutral pH. The solid,
compound LXII was dried and stored in plastic bottles at
-20.degree. C. .sup.1H NMR (400 MHz, DMSO-d6): .delta. 6.75 (s,
2H), 2.49 (s, 6H), 2.16 (s, 3H). MS (M+1): 216.15.
[0365] Synthesis of LXIV:
[0366] To a stirred solution of compound LXIII (20 g; 115.54 mmol)
in acetonitrile (360 ml) was added N-chlorosuccinimide (17 g, 127.0
mmol) portionwise at 0.degree. C. The resultant solution was
stirred at 90.degree. C. for 18 h. The reaction mixture was diluted
with water and extracted with ethyl acetate. The organic layer was
washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain the crude compound, which was purified by column
chromatography using 18% ethyl acetate in hexane to afford
6-bromo-5-chloropyridin-2-amine as off white solid (LXIV; 18 g; 75%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.42-7.40 (d,
J=8.8 Hz, 1H), 6.38-6.36 (d, J=8.8 Hz, 1H), 4.63 (bs, 2H). MS
(M+1): 206.92 (LCMS Purity 96%).
[0367] Synthesis of LXV:
[0368] To a stirred solution of compound LXIV (5 g, 24.10 mmol) in
chloroform (25 ml) was added pyridine (100 ml) at 0.degree. C.
followed by addition of 4-tert-butylbenzenesulfonyl chloride (XI,
6.71 g, 28.41 mmol). The reaction mixture was heated at 90.degree.
C. for 12 h, cooled to room temperature and concentrated under
reduced pressure. The crude mass was diluted with saturated
ammonium chloride solution and extracted with ethyl acetate. The
organic layer was washed with brine solution and dried over
anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced
pressure to afford
N-(6-bromo-5-chloropyridin-2-yl)-4-(tert-butyl)benzenesulfonamide
(LXV; 7.7 g, 79% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.82-7.80 (d, J=8.4 Hz, 2H), 7.64-7.62 (d, J=8.4 Hz, 1H), 7.51-7.49
(d, J=8.4 Hz, 2H), 7.34-7.32 (d, J=8.4 Hz, 1H), 1.37 (s, 9H). MS
(M+1): 404.89 (LCMS Purity 95%).
[0369] Synthesis of LXVI:
[0370] To a stirred solution of LXV (3 g, 7.43 mmol) in
dimethylformide (120 ml) in sealable tube was purged with argon for
20 min. Then Bis(triphenylphosphine)palladium(II) chloride (0.15 g,
0.22 mmol), copper(I)iodide (0.035 g, 0.18 mmol), triethylamine
(2.25 g, 22.29 mmol) were added. The reaction mixture was cooled
and the vessel charged with excess propyne gas for 10 min. The
reaction vessel was sealed and heated at 100.degree. C. for 24 h.
The reaction mixture was cooled and filtered through a celite bed
which was washed with ethyl acetate. All the filtrate was collected
and concentrated, diluted with water and extracted with ethyl
acetate. The organic layer was washed with brine solution and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain crude compound, which was purified by
column chromatography using 12% ethyl acetate in hexane to afford
4-(tert-butyl)-N-(5-chloro-6-(prop-1-yn-1-yl)pyridin-2-yl)benzenesulfonam-
ide (LXVI; 1.2 g, 44% yield). .sup.1H NMR (400 MHz, DMSO-d6):
.delta. 11.36 (s, 1H), 8.85-7.83 (m, 3H), 7.61-7.59 (d, J=8 Hz,
2H), 7.10-7.08 (d, J=8 Hz, 1H), 2.12 (s, 3H), 1.27 (s, 9H). MS
(M+1): 363.16. (LCMS Purity 96%).
[0371] Synthesis of LXVII:
[0372] To a stirred solution of LXVI (1.2 g, 3.30 mmol) in
dichloromethane (30 ml) was added O-(mesitylsulfonyl) hydroxylamine
(LXII; 2.84 g, 13.2 mmol). The reaction mixture was stirred for 12
h at room temperature and then diluted with water and extracted
with dichloromethane.
[0373] The organic layer was washed with a saturated aqueous
solution of sodium bicarbonate and brine solution before being
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude compound LXVII, MS (M+1):
378.16. The crude material was carried forward to the next step
without purification.
Synthesis of Compound 94:
4-(tert-butyl)-N-(4-chloro-2-methylpyrazolo[1,5-a]pyridin-7-yl)benzene
sulfonamide
[0374] To a stirred solution of LXVII (1.5 g, crude) in
dimethylformide (20 ml) was added potassium carbonate (1.6 g, 11.85
mmol). The reaction mixture was stirred at 60.degree. C. for 1 h
and then concentrated in vacuo. The residue was diluted with water
and extracted with ethyl acetate. The organic layer was washed with
brine solution and dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to obtain the crude compound,
which was purified by column chromatography using 12% ethyl acetate
in hexane to afford, the title compound (94; 0.28 g, 20% yield).
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 11.09 (bs, 1H), 7.85-7.84
(d, J=7.2 Hz, 2H), 7.58-7.56 (d, J=7.6 Hz, 2H), 7.31-7.29 (d, J=7.6
Hz, 1H), 6.63-6.61 (d, J=7.2 Hz, 1H), 6.49 (s, 1H), 2.37 (s, 3H),
1.25 (s, 9H). MS (M+1): 378.15. (LCMS Purity 97.56%, Rt=3.69 min)
(2).
Synthesis of Compound 95:
4-(tert-butyl)-N-(4-cyano-2-methylpyrazolo[1,5-a]pyridin-7-yl)benzene
sulfonamide
[0375] To a stirred solution of 94 (0.25 g, 0.66 mmol) in
dimethylacetamide (10 ml) was added Zn(CN).sub.2 (0.38 g, 3.3
mmol). The reaction mixture was purged with argon for 20 min,
whereupon 1, 1'-Bis (diphenylphosphino)ferrocene (0.01 g, 0.019
mmol), Pd2dba3 (0.009 g, 0.01 mmol) and a catalytic amount of Zn
dust were added. The reaction mixture was heated at 120.degree. C.
for 2 h in microwave reactor. The reaction mixture was cooled and
concentrated, diluted with water and extracted with
dichloromethane. The organic layer was washed with brine solution
and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain the crude compound, which was
purified by column chromatography using 2% methanol in 2%
ammoniated dichloromethane to afford the title compound (95; 0.03
g, 12% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 7.92-7.90
(d, J=8.4 Hz, 2H), 7.75-7.73 (d, J=7.6 Hz, 1H), 7.60-7.57 (d, J=8.8
Hz, 2H), 6.70-6.68 (d, J=8.0 Hz, 1H), 6.55 (s, 1H), 2.44 (s, 3H),
1.26 (s, 9H).MS (M+1): 369.22. (LCMS Purity 98.40%, Rt=6.91 min)
(2).
[0376] The following compounds were prepared in a similar manner
using the appropriate sulfonyl chloride and alkyne. The final
conversion to the nitrile was not undertaken.
TABLE-US-00011 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
96 ##STR00330## 390.04 99.09%, Rt = 4.61 min (2) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 8.07-8.05 (d, J = 8.0 Hz, 2H), 7.94-7.92
(d, J = 8.4 Hz, 2H), 7.31-7.30 (d, J = 7.6 Hz, 1H), 6.65-6.63 (d, J
= 8.0 Hz, 1H), 6.49 (s, 1H), 2.30 (s, 3H). 97 ##STR00331## 424.01
96.79%, Rt = 4.80 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
11.90 (bs, 1H), 8.25 (s, 1H), 8.05-8.03 (m, 1H), 7.88- 7.86 (d, J =
8.4 Hz, 1H), 7.35-7.33 (d, J = 8.0 Hz, 1H), 6.73-6.71 (d, J = 8.0
Hz, 1H), 6.50 (s, 1H), 2.28 (s, 3H). 98 ##STR00332## 389.37 98.91%,
Rt = 5.08 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
7.97-7.95 (d, J = 8.4 Hz, 2H), 7.72-7.70 (d, J = 8.4 Hz, 2H),
7.32-7.30 (d, J = 8.0 Hz, 1H), 6.65-6.63 (d, J = 8.0 Hz, 1H), 6.50
(s, 1H), 2.36 (s, 3H), 1.67 (s, 6H). 99 ##STR00333## 392.12. 95.97%
Rt = 5.47 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
7.85-7.83 (d, J = 8.8 Hz, 2H), 7.57-7.55 (d, J = 8.4 Hz, 2H),
7.32-7.30 (d, J = 8 Hz, 1H), 6.65-6.63 (d, J = 8 Hz, 1H), 6.52 (s,
1H), 2.76- 2.70 (q, J = 7.6 Hz, 2H), 1.25 (s, 9H), 1.2 (t, J = 7.6
Hz, 3H). 100 ##STR00334## 406.19 95.40% Rt = 5.93 min (2) .sup.1H
NMR (400 MHz, DMSO- d6): .delta. 7.84-7.82 (d, J = 8.8 Hz, 2H),
7.56-7.54 (d, J = 8.4 Hz, 2H), 7.32-7.30 (d, J = 8 Hz, 1H),
6.66-6.64 (d, J = 8 Hz, 1H), 6.52 (s, 1H), 3.08- 3.01 (m, 1H), 1.24
(s, 9H), 1.23 (m, 6H). 101 ##STR00335## 418.11 99.28%, Rt = 5.03
min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.5 (bs, 1H),
8.02- 8.00 (d, J = 8 Hz, 2H), 7.91- 7.89 (d, J = 8.4 Hz, 2H),
7.34-7.32 (d, J = 8 Hz, 1H), 6.71-6.69 (d, J = 8 Hz, 1H), 6.51 (s,
1H), 2.97-2.88 (m, 1H), 1.16-1.14 (m, 6H). 102 ##STR00336## 434.09
98.06%, Rt = 5.14 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
12.33 (bs, 1H) 7.98- 7.96 (d, J = 8.4 Hz, 2H), 7.52-7.50 (d, J =
8.4 Hz, 2H), 7.33-7.31 (d, J = 8 Hz, 1H), 6.69-6.67 (d, J = 8 Hz,
1H), 6.52 (s, 1H), 3.02-2.97 (m, 1H), 1.21-1.19 (d, J = 6.8 Hz,
6H). 103 ##STR00337## 452.04 96.24%, Rt = 5.33 min (2) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 11.39 (bs, 1H), 8.16 (s, 1H),
8.00-7.98 (d, J = 8.0 Hz, 1H), 7.87-7.85 (d, J = 8.4 Hz, 1H),
7.35-7.34 (d, J = 7.6 Hz, 1H), 6.76-6.74 (d, J = 8.4 Hz, 1H), 6.52
(s, 1H), 2.95 (m, 1H), 1.16-1.15 (d, J = 6.8 Hz, 6H). 104
##STR00338## 420.23 98.77%, Rt = 4.21 min (1) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 7.83-7.81 (d, J = 8.0 Hz, 2H), 7.54-7.52 (d, J =
8.4 Hz, 2H), 7.31-7.29 (m, 1H), 6.68-6.66 (m, 1H), 6.52 (s, 1H),
1.28 (s, 9H), 1.24 (s, 9H). 105 ##STR00339## 404.17 97.59% Rt =
5.40 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 7.84-7.82 (d,
J = 8.8 Hz 2H), 7.58-7.55 (d, J = 8.8 Hz, 2H), 7.29-7.27 (d, J =
8.4 Hz, 1H), 6.63-6.61 (d, J = 8 Hz, 1H), 6.40 (s, 1H), 2.06- 2.00
(m, 1H), 1.25 (s, 9H), 0.99-0.95 (m, 2H), 0.82-0.78 (m, 2H). 106
##STR00340## 404.10 96.86% Rt = 4.86 min (2) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 8.03 (m, 2H), 7.92 (m, 2H), 7.30 (m, 1H), 6.64
(m, 1H), 6.50 (s, 1H), 2.65-2.64 (q, J = 7.6 Hz, 2H), 1.2 (t, J =
7.6 Hz, 3H). 107 ##STR00341## 432.04 96.36%, Rt = 4.88 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 7.99-7.98 (d, J = 6 Hz,
2H), 7.54 (m, 2H), 7.30-7.28 (d, J = 5.6 Hz, 1H), 6.64 (m, 1H),
6.39 (s, 1H), 1.99-1.97 (d, J = 8 Hz, 1H), 0.95 (s, 2H), 0.75 (s,
2H). 108 ##STR00342## 450.02 95.15%, Rt = 5.06 min (2) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 8.19 (s, 1H), 8.03-8.01 (d, J = 8.4
Hz, 1H), 7.89-7.87 (d, J = 8.4 Hz, 1H), 7.32-7.30 (d, J = 8.0 Hz,
1H), 6.72-6.70 (d, J = 8.0 Hz, 1H), 6.38 (s, 1H), 1.94-1.90 (m,
1H), 0.96- 0.92 (m, 2 H), 0.68-0.66 (t, J = 5.2 Hz, 2H). 109
##STR00343## 415.12 95.94%, Rt = 4.58 min (2) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 11.52 (bs, 1H), 7.91 (s, 1H), 7.85-7.83 (d, J =
7.6 Hz, 1H), 7.79-7.77 (d, J = 7.6 Hz, 1H), 7.62-7.58 (t, J = 8.0
Hz, 1H), 7.30-7.28 (d, J = 8.0 Hz, 1H), 6.68-6.66 (d, J = 7.6 Hz,
1H), 6.37 (s, 1H), 2.01-1.99 (m, 1H), 1.67 (s, 6H), 0.96- 0.95 (m,
2H), 0.75-0.74 (m, 2H).
Example 14
Synthesis of Compound 110
[4-(tert-butyl)-N-(4-chloro-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)b-
enzenesulfonamide]; Compound 111
[3-(7-((4-(tert-butyl)phenyl)sulfonamido)-4-chloropyrazolo[1,5-a]pyridin--
2-yl)pyridine-1-oxide]; and Compounds 112 to 146
##STR00344## ##STR00345##
[0378] Synthesis of LXIX:
[0379] To a stirred solution of compound LXVIII (3 g, 21.12 mmol)
in chloroform (60 ml) was added pyridine (15 ml) at 0.degree. C.
followed by addition of 4-tert-butylbenzenesulfonyl chloride (XI,
5.89 g, 25.34 mmol). The reaction mixture was heated at 100.degree.
C. for 12 h, cooled to room temperature and concentrated under
reduced pressure. The crude material was diluted with a saturated
ammonium chloride solution and extracted with ethyl acetate. The
organic layer was washed with brine solution, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford
4-(tert-butyl)-N-(5-chloro-6-methylpyridin-2-yl)benzenesulfonamide
(LXIX; 6 g, 84% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.11 (bs, 1H), 7.86-7.84 (d, J=8.4 Hz, 2H), 7.72-7.70 (d, J=8.8
Hz, 1H), 7.60-7.58 (d, J=8.4 Hz, 2H), 6.94-6.93 (d, J=7.6 Hz, 1H),
2.36 (s, 3H), 1.27 (s, 9H). MS (M+1): 339.2.
[0380] Synthesis of LXXI:
[0381] To a stirred solution of compound LXIX (3 g; 8.87 mmol) and
ethyl nicotinate (LXX; 1.47 g; 9.75 mmol) in THF (30 ml) was added
sodium bis(trimethylsilyl)amide (26.6 ml, 1.0M in THF, 26.61 mmol)
dropwise at 0.degree. C. Upon complete addition, the resultant
solution was stirred at ambient temperature for 5 h. The reaction
mixture was diluted with a saturated solution of ammonium chloride
and extracted with ethyl acetate. The organic layer was washed with
brine solution and dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to obtain LXXI, as a
keto-enol tautomeric mixture. MS (M+1): 444.2. The crude material
was carried forward to next step without purification.
[0382] Synthesis of LXII:
[0383] To a stirred solution of compound LXXI (3 g; 6.75 mmol) in
methanol was added hydroxylamine hydrochloride (42.3 g; 33.85 mmol)
followed by a 10% aqueous solution of sodium hydroxide (22 ml). The
resultant suspension was heated at 100.degree. C. for 5 h and then
cooled to room temperature. The reaction mixture was concentrated
in vacuo and the residue was diluted with water and extracted with
ethyl acetate. The organic layer was washed with brine solution and
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain the crude compound, which was
purified by column chromatography using 50% ethyl acetate in hexane
to afford desired product (LXXII; 2.8 g; 90% yield). .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 11.64 (s, 1H), 11.03 (bs, 1H), 8.68 (s,
1H), 8.47 (m, 1H), 7.81-7.75 (m, 3H), 7.69-7.67 (d, J=8.4 Hz, 1H),
7.50-7.47 (d, J=8.4 Hz, 2H), 7.29-7.26 (m, 1H), 6.80-6.78 (d, J=8.8
Hz, 1H), 4.23 (s, 2H), 1.25 (s, 9H). MS (M+1): 459.1.
Synthesis of Compound 110;
4-(tert-butyl)-N-(4-chloro-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)be-
nzenesulfonamide
[0384] To a stirred solution of LXXII (0.15 g, 0.32 mmol) in
1,2-dimethoxyethane (7 ml) at 0.degree. C. was added trifluroacetic
anhydride (0.13 g, 0.64 mmol). The reaction mixture was allowed to
stir at 0.degree. C. for 20 minutes, followed by dropwise addition
of triethylamine (0.162 g, 1.6 mmol) in 1,2-dimethoxyethane (2 ml).
The reaction mixture was stirred at room temperature for 5 h to
generate the azirine compound LXIII in situ. To the reaction
mixture was further added iron (II) chloride (0.008 g, 0.06 mmol)
and the resultant was heated at 90.degree. C. for 2 h. The reaction
mixture was cooled and concentrated, diluted with water and
extracted with ethyl acetate. The organic layer was washed with
brine solution and dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to obtain the crude compound,
which was purified by column chromatography using 70% ethyl acetate
in hexane to afford the title compound as an off-white solid (110;
0.08 g; 57% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.19
(s, 1H), 8.60-8.59 (d, J=3.6 Hz, 1H), 8.36-8.35 (d, J=6.8 Hz, 1H),
7.82-7.80 (d, J=8.4 Hz, 2H), 7.52-7.50 (m, 3H), 7.43-7.41 (d, J=8.0
Hz, 1H), 7.31 (s, 1H), 6.85-6.83 (d, J=8.4 Hz, 1H), 1.14 (s, 9H).
MS (M+1): 441.10. (LCMS Purity 99.03%, Rt=6.09 min) (2).
Synthesis of Compound 111;
3-(7-((4-(tert-butyl)phenyl)sulfonamido)-4-chloropyrazolo[1,5-a]pyridin-2-
-yl)pyridine 1-oxide
[0385] To a stirred solution of 110 (0.1 g, 0.22 mmol) in
dichloromethane (5 ml) was added meta-chloroperbenzoic acid (0.078
g, 0.44 mmol). The reaction mixture was stirred at room temperature
for 12 h and diluted with water. The aqueous layer was extracted
with dichloromethane and the combined organic layers were washed
with a saturated solution of sodium bicarbonate, brine and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain the crude compound, which was purified
by column chromatography using 7% methanol in dichloromethane to
afford the title compound as a pink solid. (111; 0.015 g, 15%
yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 11.30 (bs, 1H),
8.93 (s, 1H), 8.25-8.23 (d, J=6 Hz, 1H), 7.95-7.93 (d, J=8 Hz, 1H),
7.82-7.79 (d, J=8.8 Hz, 2H), 7.51 (m, 3H), 7.28 (m, 2H), 6.72 (m,
1H), 1.19 (s, 9H). MS (M+1): 457.11. (LCMS Purity 95.68%, Rt=6.41
min) (2).
[0386] The following compounds were prepared in a similar manner
using the appropriate sulfonyl chloride in the first step and the
appropriate ester instead of ethyl nicotinate LXX in step 2.
[0387] Only pyridine N-oxide final compounds were subject to the
final step involving use of mCPBA.
TABLE-US-00012 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
112 ##STR00346## 469.02 97.52%, Rt = 5.79 min (2) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 9.18-9.18 (s, 1H), 8.62-8.60 (d, J = 1.6
Hz, 1H), 8.34-8.32 (d, J = 8.0 Hz, 1H), 8.02-8.00 (d, J = 8.8 Hz,
2H), 7.54-7.48 (m, 3H), 7.43-7.41 (d, J = 8.0 Hz, 1H), 7.27 (s,
1H), 6.84- 6.82 (d, J = 8.0 Hz, 1H) 113 ##STR00347## 453.03 98.63%,
Rt = 5.73 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 9.13 (s,
1H) 8.61 (bs, 1H), 8.25 (m, 1H), 8.13 (m, 2H), 7.89 (m, 2H), 7.52
(m, 2H), 7.37-7.33 (s, 1H), 6.83 (m, 1H) 114 ##STR00348## 487.09
96.32%, Rt = 5.89 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
9.15 (s, 1H) 8.63-8.62 (d, J = 4.8 Hz, 1H) 8.28-8.26 (d, J = 8 Hz,
1H), 8.19 (s, 1H), 8.09-8.07 (d, J = 8.0 Hz, 1H), 7.85-7.83 (d, J =
8.0 Hz, 1H), 7.54-7.51 (m, 1H), 7.42-7.39 (m, 1H), 7.31 (s, 1H),
6.81-6.79 (d, J = 7.6 Hz, 1H) 115 ##STR00349## 403.01 95.78%, Rt =
5.05 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 9.22 (s, 1H)
8.63-8.62 (d, J = 3.6 Hz, 1H) 8.39-8.37 (d, J = 8.4 Hz 1H),
8.04-7.97 (m, 2H), 7.56-7.53 (m, 1H), 7.48-7.35 (m, 4H), 6.82-6.80
(d, J = 8.0 Hz, 1H). 116 ##STR00350## 485.14 98.93%, Rt = 6.06 min
(2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 8.84 (s, 1H) 8.22-8.21
(d, J = 6.0 Hz, 1H) 7.95-7.93 (m, 3H), 7.51-7.48 (t, J = 7.2 Hz,
1H), 7.43-7.41 (d, J = 8.4 Hz, 2H), 7.15 (m, 2H), 6.46 (m, 1H). 117
##STR00351## 399.17 95.01%, Rt = 5.06 min (1) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 11.35 (bs, 1H) 9.22 (s, 1H), 8.60 (m, 1H),
8.38-8.36 (d, J = 6.4 Hz, 1H), 7.81- 7.76 (m, 2H), 7.51 (m, 1H),
7.35-7.26 (m, 4H), 6.69 (m, 1H), 2.28 (s, 3H). 118 ##STR00352##
502.87 96.08%, Rt = 6.19 min (2) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 8.82 (s, 1H), 8.22-8.21 (d, J = 5.6 Hz, 1H), 8.17 (s, 1H),
8.07-8.04 (d, J = 8.4 Hz, 1H), 7.96-7.94 (d, J = 8.0 Hz, 1H),
7.80-7.78 (d J = 8.4 Hz, 1H), 7.52-7.48 (t, J = 7.2 Hz, 1H), 7.12
(s, 2H), 6.34 (bs, 1H). 119 ##STR00353## 419.22 96.07%, Rt = 4.65
min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 8.86 (s, 1H),
8.23-8.21 (d, J = 4.8 Hz, 1H), 7.97- 7.89 (m, 3H), 7.55-7.49 (m,
1H), 7.29-7.27 (d, J = 7.6 Hz, 2H), 7.08 (m, 2H), 6.49- 6.37 (m,
1H). 120 ##STR00354## 413.17 (M - 1) 98.46%, Rt = 4.95 min (1)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.36 (bs, 1H), 9.25 (s,
1H), 8.61-8.60 (d, J = 3.2 Hz, 1H), 8.41-8.39 (d, J = 6.4 Hz, 1H),
7.87-7.85 (d, J = 8.0 Hz, 2H), 7.52 (m, 1H), 7.39-7.37 (d, J = 8
Hz, 1H), 7.30 (s, 1H), 7.04-7.02 (d, J = 8.8 Hz, 2H), 6.76-6.74 (d,
J = 6.0 Hz, 1H), 3.74 (s, 3H). 121 ##STR00355## 469.04 95.69%, Rt =
4.95 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 8.83 (s, 1H),
8.23-8.21 (d, J = 6 Hz, 1H), 8.03-8.01 (d, J = 8 Hz, 2H), 7.90-7.89
(d, J = 7.2 Hz, 1H), 7.84- 7.82 (d, J = 7.6 Hz, 2H), 7.51-7.47 (t,
J = 7.2 Hz, 1H), 7.21 (m, 2H), 6.56 (s, 1H). 122 ##STR00356##
450.22 (M - 1) 95.94%, Rt = 4.70 min (1) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 11.65 (bs, 1H), 9.19 (s, 1H), 8.56-8.53 (d, J =
8 Hz, 1H), 8.49 (s, 1H), 8.31- 8.30 (d, J = 5.6 Hz, 1H), 7.99-7.97
(d, J = 8 Hz, 2H), 7.86-7.84 (d, J = 7.2 Hz, 2H), 7.79 (s, 1H),
7.46 (m, 1H), 7.42-7.40 (d, J = 7.6 Hz, 1H), 7.32 (s, 1H), 6.83-
6.81 (d, J = 7.6 Hz, 1H). 123 ##STR00357## 452.08 98.75%, Rt = 5.63
min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.52 (bs, 1H),
9.15 (s, 1H), 8.60 (m, 1H), 8.32 (m, 1H), 7.92 (m, 2H), 7.65 (m,
2H), 7.50 (m, 1H), 7.39 (m, 1H), 7.27 (s, 1H), 6.80 (m, 1H), 1.55
(s, 6H). 124 ##STR00358## 427.12 98.23%, Rt = 6.21 min (2) .sup.1H
NMR (400 MHz, DMSO- d6): .delta. 11.23 (bs, 1H), 9.20 (s, 1H), 8.60
(d, J = 3.6 Hz, 1H), 8.37-8.35 (d, J = 7.6 Hz, 1H), 7.82-7.80 (d, J
= 8.0 Hz, 2H), 7.53-7.50 (m, 1H), 7.43-7.37 (m, 3H), 7.32 (s, 1H),
6.84-6.82 (d, J = 8.0 Hz, 1H), 2.88-2.81 (m, 1H), 1.07-1.05 (d, J =
6.8 Hz, 6H). 125 ##STR00359## 455.10 (M - 1) 96.43% Rt = 5.64 min
(1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.27 (bs, 1H), 8.81
(s, 1H), 8.32-8.32 (d, J = 2.8 Hz, 1H), 7.95 (s, 1H), 7.82- 7.80
(d, J = 8.4 Hz, 2H), 7.43-7.36 (m, 4H), 6.84-6.82 (d, J = 8.0 Hz,
1H), 3.93 (s, 3H), 2.88-2.81 (m, 1H), 1.07-1.05 (d, J = 6.8 Hz, 6H)
126 ##STR00360## 473.36 95.05% Rt = 5.18 min (1) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 11.44 (bs, 1H), 8.65 (s, 1H), 8.08 (s, 1H),
7.83- 7.81 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.45-7.44 (d, J = 4.8
Hz, 1H), 7.42 (s, 1H), 7.40-7.38 (d, J = 8.0 Hz, 2H), 6.89-6.87 (d,
J = 8.0 Hz, 1H), 3.91 (s, 3H), 2.93- 2.82 (m, 1H), 1.10-1.08 (d, J
= 6.8 Hz, 6H). 127 ##STR00361## 471.12 98.06%, Rt = 6.79 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.32 (bs, 1H), 8.80 (s,
1H), 8.32-8.31 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.81-7.79 (d, J =
8.4 Hz, 2H), 7.52-7.49 (d, J = 8.4 Hz, 2H), 7.43-7.41 (d, J = 8.0
Hz, 1H), 7.37 (s, 1H), 6.85-6.83 (d, J = 8.0 Hz, 1H), 3.93 (s, 3H),
1.14 (s, 9H). 128 ##STR00362## 483.34 98.57%, Rt = 5.54 min (1)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 8.72-8.72 (d, J = 1.6 Hz,
1H), 8.32-8.31 (d, J = 2.8 Hz, 1H), 8.07-8.05 (d, J = 8.0 Hz, 2H),
7.88-7.84 (m, 3H), 7.42-7.40 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H),
6.82-6.80 (d, J = 7.6 Hz, 1H), 3.92 (s, 3H). 129 ##STR00363##
517.28 96.22%, Rt = 5.80 min (1) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 8.72 (s, 1H), 8.34-8.33 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H),
8.11-8.08 (dd, J = 1.6, 2.4 Hz, 1H), 7.88 (s, 1H), 7.85-7.83 (d, J
= 8.4 Hz, 1H), 7.42-7.40 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H),
6.85-6.83 (d, J = 8.0 Hz, 1H), 3.93 (s, 3H). 130 ##STR00364##
499.32 94.22%, Rt = 5.65 min (1) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 8.78 (s, 1H), 8.32 (s, 1H), 8.01-7.99 (d, J = 8.0 Hz, 2H),
7.89 (s, 1H), 7.49- 7.47 (d, J = 8.4 Hz, 2H), 7.42-7.40 (d, J = 7.6
Hz, 1H), 7.37 (s, 1H), 6.83-6.81 (d, J = 8.0 Hz, 1H), 3.93 (s, 3H).
131 ##STR00365## 515.29 95.01%, Rt = 5.26 min (1) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 8.61 (s, 1H), 8.09 (s, 1H), 8.02-8.00 (d, J
= 8.8 Hz, 2H), 7.61 (s, 1H), 7.51- 7.49 (d, J = 8.0 Hz, 2H), 7.43
(m, 2H), 6.84 (m, 1H), 3.91 (s, 3H). 132 ##STR00366## 459.13 97.87%
Rt = 5.09 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.25
(bs, 1H), 9.09 (s, 1H), 8.62-8.61 (d, J = 2.8 Hz, 1H), 8.32-8.29
(d, J = 10.4 Hz, 1H), 7.82-7.80 (d, J = 8.4 Hz, 2H), 7.53-7.51 (d,
J = 8.4 Hz, 2H), 7.45-7.43 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H),
6.89-6.87 (d, J = 8.0 Hz, 1H), 1.15 (s, 9H). 133 ##STR00367##
471.31 99.85%, Rt = 5.61 min (1) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 9.00 (s, 1H), 8.61-8.60 (d, J = 2.4 Hz, 1H), 8.12-8.10 (d,
J = 10.0 Hz, 1H), 8.07- 8.05 (d, J = 8.4 Hz, 2H), 7.89- 7.87 (d, J
= 8.4 Hz, 2H), 7.45- 7.40 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H),
6.88-6.86 (d, J = 7.8 Hz, 1H). 134 ##STR00368## 475.34 99.54% Rt =
6.21 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 9.16 (s, 1H),
8.65-8.64 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 7.79-7.77 (d, J = 8.4
Hz, 2H), 7.50-7.48 (d, J = 8.4 Hz, 2H), 7.35 (m, 2H), 6.78 (m, 1H),
1.16 (s, 9H). 135 ##STR00369## 441.40 96.77% Rt = 5.64 min (1)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.58 (bs, 1H), 8.69- 8.68
(d, J = 5.2 Hz, 2H), 8.00- 7.99 (d, J = 5.6 Hz, 2H), 7.81- 7.79 (d,
J = 8.4 Hz, 2H), 7.52- 7.50 (d, J = 8.4 Hz, 2H), 7.44- 7.39 (m,
2H), 6.86-6.84 (d, J = 8.0 Hz, 1H), 1.14 (s, 9H). 136 ##STR00370##
471.14 98.38% Rt = 5.20 min (2) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 11.20 (bs, 1H), 8.25- 8.24 (d, J = 5.2 Hz, 1H), 7.81- 7.79
(d, J = 8.0 Hz, 2H), 7.58-7.56 (d, J = 5.2 Hz, 1H), 7.52-7.50 (d, J
= 8.4 Hz, 2H), 7.43-7.41 (d, J = 9.6 Hz, 2H), 7.36 (s, 1H),
6.87-6.85 (d, J = 8 Hz, 1H), 3.90 (s, 3H), 1.15 (s, 9H) 137
##STR00371## 441.36 99.52% Rt = 5.75 min (1) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 8.65-8.64 (d, J = 4.4 Hz, 1H), 8.12-8.10 (d, J =
7.6 Hz, 1H), 7.96-7.92 (t, J = 7.6 Hz, 1H), 7.82-7.80 (d, J = 8.4
Hz, 2H), 7.52-7.50 (d, J = 8.4 Hz, 2H), 7.43-7.39 (m, 2H), 7.13 (s,
1H), 6.82-6.81 (d, J = 7.6 Hz, 1H), 1.14 (s, 9H). 138 ##STR00372##
491.20 99.63% Rt = 6.23 min (1) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 11.37 (bs, 1H), 9.54- 9.53 (d, J = 2.0 Hz, 1H), 8.94 (s,
1H), 8.08-8.06 (d, J = 8.4 Hz, 2H), 7.86-7.79 (m, 3H), 7.70-7.66
(t, J = 6.8 Hz, 1H), 7.53-7.51 (d, J = 8.4 Hz, 2H), 7.46-7.44 (d, J
= 6.0 Hz, 2H), 6.87-6.85 (d, J = 8.0 Hz, 1H), 1.09 (s, 9H). 139
##STR00373## 442.37 99.53% Rt = 5.43 min (1) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 9.80 (s, 1H), 9.34-9.33 (d, J = 5.2 Hz, 1H),
8.20 (s, 1H), 7.79-7.77 (d, J = 8.4 Hz, 2H), 7.50-7.48 (m, 3H),
7.43 (s, 1H), 6.83-6.80 (d, J = 14.0 Hz, 1H), 1.14 (s, 9H). 140
##STR00374## 440.11 97.97% Rt = 5.84 min (2) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 8.02-8.00 (d, J = 7.2 Hz, 2H), 7.84-7.82 (d, J =
8.4 Hz, 2H), 7.54-7.52 (d, J = 8.8 Hz, 2H), 7.48-7.45 (m, 2H),
7.42-7.37 (m, 2H), 7.16 (s, 1H), 6.79-6.77 (d, J = 8.0 Hz, 1H),
1.16 (s, 9H) 141 ##STR00375## 454.41 98.56% Rt = 6.64 (1) .sup.1H
NMR (400 MHz, DMSO- d6): .delta. 11.35 (bs, 1H), 7.87- 7.83 (m,
3H), 7.80-7.79 (d, J = 6.8 Hz, 1H), 7.54-7.52 (d, J = 8.4 Hz, 2H),
7.39-7.33 (m, 2H), 7.23-7.21 (d, J = 6.8 Hz, 1H), 7.15 (s, 1H),
6.78-6.76 (d, J = 8.0 Hz, 1H), 2.34 (s, 3H), 1.16 (s, 9H). 142
##STR00376## 444.13 98.64% Rt = 4.66 min (1) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 11.30 (bs, 1H), 8.16 (s, 1H), 7.85-7.83 (m, 3H),
7.56- 7.54 (d, J = 7.2 Hz, 2H), 7.34- 7.32 (d, J = 7.2 Hz, 1H),
6.85 (s, 1H), 6.68-6.66 (d, J = 7.2 Hz, 1H), 3.89 (s, 3H), 1.20 (s,
9H). 143 ##STR00377## 444.17 98.83% Rt = 4.86 min (1) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 11.28 (bs, 1H), 7.75- 7.73 (d, J = 8.8
Hz, 2H), 7.52- 7.50 (d, J = 8.4 Hz, 2H), 7.46- 7.44 (d, J = 8.4 Hz,
2H), 7.06 (s, 1H), 6.86-6.84 (d, J = 8 Hz, 1H), 6.80-6.79 (d, J = 2
Hz, 1H), 4.09 (s, 3H), 1.17 (s, 9H). 144 ##STR00378## 458.40 99.64%
Rt = 5.91 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.29
(bs, 1H), 7.76- 7.74 (d, J = 8.4 Hz, 2H), 7.52- 7.50 (d, J = 8.8
Hz, 2H), 7.45- 7.43 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.84-6.82
(d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 4.00 (s, 3H), 2.16 (s, 3H), 1.18
(s, 9H). 145 ##STR00379## 444.46 95.53% Rt = 5.32 min (1) .sup.1H
NMR (400 MHz, DMSO- d6): .delta. 8.18 (s, 1H), 7.75-7.69 (m, 3H),
7.49-7.47 (d, J = 5.6 Hz, 2H), 7.31-7.30 (d, J = 6.4 Hz, 1H), 6.93
(s, 1H), 6.65- 6.63 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 1.20 (s,
9H). 146 ##STR00380## 461.27 99.66% Rt = 6.0 min (1) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 9.41 (bs, 1H), 7.86-7.80 (m, 2H),
7.57-7.55 (d, J = 8.4 Hz, 2H), 7.37-7.31 (m, 1H), 6.75-6.55 (m,
2H), 3.55 (m, 1H), 3.39-2.99 (m, 4H), 2.83 (s, 3H), 2.24-2.21 (m,
2H), 2.07-1.80 (m, 2H), 1.25 (s, 9H).
Example 15
Synthesis of Compound 147
[4-(tert-butyl)-N-(4-chloro-2-(1H-imidazol-4-yl)pyrazolo[1,5-a]pyridin-7--
yl)benzenesulfonamide] and Compound 148
##STR00381## ##STR00382##
[0389] Synthesis of LXXV:
[0390] To a stirred solution of compound LXIX (3 g; 8.87 mmol) and
ethyl 1-trityl-1H-imidazole-4-carboxylate (XLV; 10 g; 26.62 mmol)
in THF (50 ml) was added sodium bis(trimethylsilyl)amide (44 ml,
1.0 M in THF, 44.35 mmol) dropwise at 0.degree. C. Upon complete
addition, the resultant solution was stirred at ambient temperature
for 2 h. The reaction mixture was diluted with a saturated solution
of ammonium chloride and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain
4-(tert-butyl)-N-(5-chloro-6-(2-oxo-2-(1-trityl-1H-imidazol-4-yl)ethyl)py-
ridin-2-yl)benzenesulfonamide LXXV, as a keto-enol tautomeric
mixture. MS (M+1): 675.12. The crude material was carried forward
to next step without purification.
[0391] Synthesis of LXXVI:
[0392] To a stirred solution of compound LXXV (6 g, tautomeric
mixture) in methanol (60 ml) was added hydroxylamine hydrochloride
(1.9 g; 26.7 mmol) followed by a 10% aqueous solution of sodium
hydroxide (36 ml). The resultant suspension was heated at
100.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain the crude compound which was purified by column
chromatography using 100% ethyl acetate to afford the desired
product
4-(tert-butyl)-N-(5-chloro-6-(2-(hydroxyimino)-2-(1-trityl-1H-imidazol-4--
yl)ethyl)pyridin-2-yl)benzenesulfonamide as a white solid (LXXVI; 4
g; 67% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 10.93 (bs,
1H), 10.79 (bs, 1H), 7.86-7.84 (d, J=8 Hz, 2H), 7.65-7.63 (d, J=8.8
Hz, 1H), 7.48-7.46 (m, 2H), 7.34 (m, 10H), 7.05 (m, 6H), 6.92 (s,
1H), 6.76-6.74 (m, 1H), 4.16 (s, 2H), 1.20 (s, 9H). MS (M+1):
690.11.
[0393] Synthesis of LXXVIII:
[0394] To a stirred solution of compound LXXVI (1 g, 1.45 mmol) in
1,2-dimethoxyethane (20 ml) at 0.degree. C. was added
trifluroacetic anhydride (0.9 g, 4.35 mmol). The reaction mixture
was allowed to stir at 0.degree. C. for 20 minutes, followed by
dropwise addition of triethylamine (2.93 g, 29 mmol) in
1,2-dimethoxyethane (10 ml). The reaction mixture was stirred at
room temperature for 1 h to leave LXXVII prepared in situ. To the
reaction mixture was further added iron (II) chloride (0.07 g, 0.58
mmol) and this was heated at 100.degree. C. for 3 h. The reaction
mixture was cooled and concentrated, diluted with water and
extracted with dichloromethane. The organic layer was washed with
brine solution and dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to obtain crude compound,
which was purified by column chromatography using 2% methanol in
dichloromethane to afford the title compound (LXXVIII; 0.6 g; 67%
yield). MS (M-1): 670.11.
Synthesis of Compound 147:
4-(tert-butyl)-N-(4-chloro-2-(1H-imidazol-4-yl)pyrazolo[1,5-a]pyridin-7-y-
l)benzenesulfonamide
[0395] To a stirred solution of compound LXXVIII, (0.25 g, 0.37
mmol) in water (5 ml) at 0.degree. C. was added trifluoroacetic
acid (5 ml). The resultant solution was allowed to stir at
0.degree. C. for 15 min. The reaction mixture was concentrated
under reduced pressure to obtain the crude compound, which was
purified by preparative HPLC to afford the title compound 147,
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.54 (s, 1H), 7.92 (s, 1H),
7.77-7.75 (d, J=8 Hz, 2H), 7.48-7.46 (d, J=8.4 Hz, 2H), 7.18-7.16
(d, J=8.4 Hz, 1H), 6.86 (s, 1H), 6.45-6.43 (d, J=8.8 Hz, 1H), 1.22
(s, 9H). MS (M+1): 430.15. (LCMS purity 97.87%, Rt=5.75 min)
(2).
TABLE-US-00013 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
148 ##STR00383## 430.13 98.89% Rt = 6.78 min (1) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 13.06 (bs, 1H), 8.06 (m, 2H), 7.85-7.83 (d,
J = 8.4 Hz, 2H), 7.55-7.53 (d, J = 8.4 Hz, 2H), 7.34-7.32 (d, J =
8.0 Hz, 1H), 6.89 (s, 1H), 6.68-6.66 (d, J = 8.0 Hz, 1H), 1.19 (s,
9H).
Example 16
Synthesis of Compound 149
[4-(tert-butyl)-N-(4-cyano-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)be-
nzenesulfonamide] and Compounds 150 to 152
##STR00384##
[0397] To a stirred solution of 110 (0.15 g, 0.34 mmol) in
dimethylacetamide (5 ml) was added Zn(CN).sub.2 (0.079 g, 0.68
mmol). The reaction mixture was purged with argon for 20 minutes.
To the reaction mixture was then added 1, 1'-Bis
(diphenylphosphino)ferrocene (0.038 g, 0.068 mmol),
Pd.sub.2dba.sub.3 (0.047 g, 0.051 mmol) and a catalytic amount of
Zn dust. The reaction mixture was heated at 120.degree. C. for 2 h
in a microwave reactor. The reaction mixture was cooled and
concentrated, diluted with water and extracted with
dichloromethane. The organic layer was washed with brine solution
and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain material which was purified by
column chromatography using 2% methanol in 2% ammoniated
dichloromethane. This afforded the title compound (149; 0.015 g,
10% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.32 (s, 1H),
8.66-8.65 (m, 1H), 8.60-8.58 (d, J=8.0 Hz, 1H), 7.84-7.82 (d, J=8.4
Hz, 2H), 7.65-7.62 (m, 2H), 7.54-7.51 (d, J=8.4 Hz, 2H), 7.23 (s,
1H), 6.62-6.60 (d, J=8.4 Hz, 1H), 1.25 (s, 9H). MS (M+1): 432.44.
(LCMS Purity 96.63%, Rt=5.36 min) (1).
[0398] The following compounds were prepared from the analogous
chloro compounds prepared in the examples above.
TABLE-US-00014 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
150 ##STR00385## 432.22 99.28% Rt = 5.69 min (2) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 8.69-8.68 (d, J = 5.6 Hz, 2H), 8.11-8.10
(d, J = 4.8 Hz, 2H), 7.77-7.75 (d, J = 8.4 Hz, 2H), 7.53 (d, J =
8.4 Hz, 1H), 7.49-7.47 (d, J = 8.4 Hz, 2H), 7.15 (s, 1H), 6.46-6.44
(d, J = 8.8 Hz, 1H), 1.23 (s, 9H). 151 ##STR00386## 433.12 98.49%
Rt = 5.0 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 9.84 (s,
1H), 9.29-9.28 (d, J = 5.6 Hz, 1H), 8.24-8.23 (m, 1H), 7.77-7.75
(d, J = 8 Hz, 2H), 7.54-7.52 (d, J = 8.4 Hz, 1H), 7.49-7.47 (d, J =
8.4 Hz, 2H), 7.27 (s, 1H), 6.47-6.45 (d, J = 8.4 Hz, 1H), 1.25 (s,
9H). 152 ##STR00387## 435.14 99.83% Rt = 5.19 min (1) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 7.83-7.80 (d, J = 8.4 Hz, 2H),
7.67-7.65 (d, J = 7.6 Hz, 1H), 7.53-7.48 (m, 3H), 6.92 (s, 1H),
6.81 (m, 1H), 6.62-6.60 (d, J = 8.8 Hz, 1H), 4.19 (s, 3H), 1.24 (s,
9H).
Example 17
Synthesis of Compound 153
[4-(tert-butyl)-N-(4-chloro-2-(5-cyanopyridin-3-yl)pyrazolo[1,5-a]pyridin-
-7-yl)benzenesulfonamide]
##STR00388##
[0400] Compound LXXIX was synthesized from LXIX and ethyl
5-bromonicotinate essentially as described in Example 14.
[0401] To a stirred solution of compound LXXIX, (0.2 g, 0.39 mmol)
in dimethylacetamide (5 ml) was added Zn(CN).sub.2 (0.09 g, 0.78
mmol). The reaction mixture was purged with argon for 20 minutes
followed by addition of 1, 1'-Bis (diphenylphosphino)ferrocene
(0.044 g, 0.078 mmol), Pd2dba3 (0.036 g, 0.039 mmol) and a
catalytic amount of Zn dust. The reaction mixture was heated at
120.degree. C. for 2 h in a microwave reactor. The reaction mixture
was cooled and filtered through a celite bed. The filtrate was
concentrated, diluted with water and extracted with
dichloromethane. The organic layer was washed with brine solution
and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain the crude compound, which was
purified by column chromatography using 2% methanol in 10%
ammoniated dichloromethane to afford the title compound (153; 0.015
g, 9% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 11.36 (bs,
1H), 9.47-9.46 (d, J=2 Hz, 1H), 9.06-9.05 (d, J=2 Hz, 1H),
8.93-8.92 (m, 1H), 7.84-7.82 (d, J=8.4 Hz, 2H), 7.54-7.52 (d, J=8.4
Hz, 2H), 7.47-7.45 (d, J=8.0 Hz, 2H) 6.92-6.90 (d, J=8.0 Hz, 1H),
1.16 (s, 9H). MS (M+1): 466.42. (LCMS Purity 99.57%, Rt=5.84 min)
(1).
Example 18
Synthesis of Compound 154
[4-(tert-butyl)-N-(4-cyano-2-(5-cyanopyridin-3-yl)pyrazolo[1,5-a]pyridin--
7-yl)benzenesulfonamide]
##STR00389## ##STR00390##
[0403] Synthesis of LXXXI:
[0404] To a stirred solution of compound LXXX (12 g, 64.15 mmol) in
chloroform (120 ml) was added pyridine (25 ml) at 0.degree. C.
followed by addition of 4-tert-butylbenzenesulfonyl chloride (XI,
17.92 g, 76.98 mmol). The reaction mixture was heated at 80.degree.
C. for 4 h, cooled to room temperature and concentrated under
reduced pressure. The crude mass was diluted with a saturated
ammonium chloride solution and extracted with ethyl acetate. The
organic layer was washed with brine solution, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford
N-(5-bromo-6-methylpyridin-2-yl)-4-(tert-butyl)benzenesulfonamide
(LXXXI, 22 g, 89% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.14 (bs, 1H), 7.86-7.82 (m, 3H), 7.60-7.58 (d, J=8.4 Hz, 2H),
6.87-6.85 (d, J=10.4 Hz, 1H), 2.39 (s, 3H), 1.27 (s, 9H). MS (M+1):
383.2.
[0405] Synthesis of LXXXII:
[0406] To a stirred solution of compound LXXXI (2 g; 5.21 mmol) and
ethyl 5-bromonicotinate (2.39 g; 10.42 mmol) in THF (50 ml) was
added sodium bis(trimethylsilyl)amide (13.02 ml, 1.0 M in THF,
13.02 mmol) dropwise at 0.degree. C. Upon complete addition, the
resultant solution was stirred at ambient temperature for 4 h. The
reaction mixture was diluted with a saturated solution of ammonium
chloride and extracted with ethyl acetate. The organic layer was
washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain LXXXII,
N-(5-bromo-6-(2-(5-bromopyridin-3-yl)-2-oxoethyl)pyridin-2-yl)-4-(tert-bu-
tyl) benzene sulfonamide, as a keto-enol tautomeric mixture. MS
(M+1): 566.2. The crude material was carried forward to next step
without purification.
[0407] Synthesis of LXXXIII:
[0408] To a stirred solution of compound LXXXII (2.3 g, tautomeric
mixture) in methanol (100 ml) was added hydroxylamine hydrochloride
(2.7 g; 40.29 mmol) followed by a 10% aqueous solution of sodium
hydroxide (25 ml). The resultant suspension was heated at
80.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with dichloromethane. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and was evaporated under reduced
pressure to obtain crude compound, which was purified by column
chromatography using 35% ethyl acetate in hexane to afford desired
product
N-(6-(2-(5-bromopyridin-3-yl)-2-(hydroxyimino)ethyl)-5-chloropyri-
din-2-yl)-4-(tert-butyl)benzenesulfonamide as white solid (LXXXIII;
1.5 g; 69% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.79 (s,
1H), 11.01 (bs, 1H), 8.67 (s, 1H), 8.64-8.63 (d, J=2 Hz, 1H), 8.07
(d, J=2 Hz, 1H), 7.85-7.83 (d, J=8.8 Hz, 1H), 7.69-7.67 (m, 2H),
7.47-7.45 (m, 2H), 6.73-6.71 (d, J=8.4 Hz, 1H), 4.23 (s, 2H), 1.25
(s, 9H). MS (M+1): 537.1 (LCMS Purity 95%).
[0409] Synthesis of LXXXV:
[0410] To a stirred solution of LXXXIII (1 g, 1.71 mmol) in
1,2-dimethoxyethane (30 ml) at 0.degree. C. was added
trifluroacetic anhydride (0.72 g, 3.42 mmol). The reaction mixture
was allowed to stir for 20 minutes, followed by dropwise addition
of triethylamine (1.73 g, 17.1 mmol) in 1,2-dimethoxyethane (5 ml).
The reaction mixture was stirred at room temperature for 1 h to
generate LXXXIV in situ. To the reaction mixture was added iron
(II) chloride (0.043 g, 0.34 mmol) and heated at 100.degree. C. for
3 h. The reaction mixture was cooled and concentrated, diluted with
water and extracted with dichloromethane. The organic layer was
washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by column chromatography
using 2% methanol in dichloromethane to afford
N-(4-bromo-2-(5-bromopyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-bu-
tyl)benzenesulfonamide as off white solid (LXXXV; 0.5 g; 50%
yield).
Synthesis of Compound 154;
4-(tert-butyl)-N-(4-cyano-2-(5-cyanopyridin-3-yl)pyrazolo[1,5-a]pyridin-7-
-yl)benzenesulfonamide
[0411] To a stirred solution of LXXXV (0.3 g, 0.53 mmol) in
dimethylacetamide (5 ml) was added Zn(CN).sub.2 (0.31 g, 2.65
mmol). The reaction mixture was purged with argon for 20 min and 1,
1'-Bis (diphenylphosphino)ferrocene (0.08 g, 0.16 mmol), Pd2dba3
(0.09 g, 0.1 mmol) and catalytic amount of Zn dust were added. The
reaction mixture was heated at 120.degree. C. for 2 h in a
microwave reactor. The reaction mixture was cooled and
concentrated, diluted with water and extracted with
dichloromethane. The organic layer was washed with brine solution
and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude compound, which was purified
by column chromatography using 1% methanol in dichloromethane to
afford the title compound as an off white solid (154; 0.08 g, 33%
yield).
[0412] .sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.54 (s, 1H), 9.04
(s, 1H), 8.94 (s, 1H), 7.85-7.83 (d, J=8.4 Hz, 2H), 7.69-7.67 (d,
J=8.0 Hz, 1H), 7.55-7.53 (d, J=8.0 Hz, 2H), 7.36 (s, 1H), 6.67-6.65
(d, J=8.0 Hz, 1H), 1.23 (s, 9H). MS (M+1): 457.44. (LCMS Purity
96.01%, Rt=5.63 min) (1).
Example 19
Synthesis of Compound 155
[N-(4-bromo-2-(5-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert--
butyl)benzenesulfonamide]; Compound 156
[4-(tert-butyl)-N-(4-cyano-2-(5-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-
-7-yl)benzenesulfonamide] and Compounds 157 to 161
##STR00391##
[0414] Synthesis of LXXXVI:
[0415] To a stirred solution of compound LXXXI (2.5 g; 6.54 mmol)
and ethyl 5-fluoronicotinate (2.2 g; 13.08 mmol) in THF (30 ml) was
added sodium bis(trimethylsilyl)amide (19.7 ml, 1.0M in THF, 19.62
mmol) dropwise at 0.degree. C. Upon complete addition, the
resultant solution was stirred at ambient temperature for 4 h. The
reaction mixture was diluted with a saturated solution of ammonium
chloride and extracted with ethyl acetate. The separated organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain LXXXVI,
N-(5-bromo-6-(2-(5-fluoropyridin-3-yl)-2-oxoethyl)pyridin-2-yl)-4-(tert-b-
utyl)benzenesulfonamide as a keto-enol tautomeric mixture. MS
(M+1): 506.10. The crude material was carried forward to the next
step without purification.
[0416] Synthesis of LXXXVII:
[0417] To a stirred solution of compound LXXXVI (2.4 g, tautomeric
mixture) in methanol (100 ml) was added hydroxylamine hydrochloride
(1.64 g; 23.71 mmol) followed by a 10% aqueous solution of sodium
hydroxide (20 ml). The resultant suspension was heated at
100.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and was evaporated under reduced
pressure to obtain the crude compound, which was purified by column
chromatography using 15% ethyl acetate in hexane to afford desired
product
N-(5-bromo-6-(2-(5-fluoropyridin-3-yl)-2-(hydroxyimino)ethyl)pyri-
din-2-yl)-4-(tert-butyl)benzenesulfonamide as off white solid
(LXXXVII; 1.2 g; 48% yield). MS (M+1): 521.1 (LCMS Purity 96%).
Synthesis of Compound 155;
N-(4-bromo-2-(5-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-b-
utyl)benzenesulfonamide
[0418] To a stirred solution of LXXXVII (1.2 g, 2.30 mmol) in
1,2-dimethoxyethane (22 ml) at 0.degree. C. was added
trifluroacetic anhydride (0.96 g, 4.60 mmol). The reaction mixture
was allowed to stir at 0.degree. C. for 20 minutes, followed by the
dropwise addition of triethylamine (2.32 g, 23.0 mmol) in
1,2-dimethoxyethane (10 ml). The reaction mixture was stirred at
room temperature for 1.5 h forming LXXXVIII in situ. To the
reaction mixture was added iron (II) chloride (0.11 g, 0.92 mmol)
and this was heated at 100.degree. C. for 3 h. The reaction mixture
was cooled and concentrated, diluted with water and extracted with
ethyl acetate. The organic layer was washed with brine solution and
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude compound, which was purified
by column chromatography using 12% ethyl acetate in hexane to
afford the title compound as an off white solid. (155; 0.4 g; 35%
yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 11.22 (bs, 1H),
9.10 (s, 1H), 8.61-8.61 (d, J=2.8 Hz, 1H), 8.34-8.32 (d, J=10.0 Hz,
1H), 7.83-7.81 (d, J=8.4 Hz, 2H), 7.58-7.52 (m, 3H), 7.35 (s, 1H),
6.85-6.83 (d, J=8.0 Hz, 1H), 1.16 (s, 9H). MS (M-1): 501.28. (LCMS
Purity 98.28%, Rt=5.91 min) (1).
Synthesis of Compound 156;
4-(tert-butyl)-N-(4-cyano-2-(5-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin--
7-yl)benzenesulfonamide
[0419] To a stirred solution of 114 (0.2 g, 0.39 mmol) in
dimethylacetamide (10 ml) was added Zn(CN).sub.2 (0.09 g, 0.78
mmol). The reaction mixture was purged with argon for 20 minute.
Then, 1, 1'-Bis (diphenylphosphino)ferrocene (0.043 g, 0.078 mmol),
Pd.sub.2dba.sub.3 (0.054 g, 0.058 mmol) and a catalytic amount of
Zn dust were added. The reaction mixture was heated at 120.degree.
C. for 2 h in a microwave reactor. The reaction mixture was cooled
and concentrated, diluted with water and extracted with
dichloromethane. The organic layer was washed with brine solution
and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude compound, which was purified
by column chromatography using 5% methanol in dichloromethane and
10% ammonia hydroxide to afford the title compound (156; 0.06 g,
33% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.16 (s, 1H),
8.61-8.60 (d, J=2.4 Hz, 1H), 8.37-8.34 (d, J=10.0 Hz, 1H),
7.83-7.81 (d, J=8.0 Hz, 2H), 7.65-7.63 (d, J=8.4 Hz, 1H), 7.54-7.51
(d, J=8.4 Hz, 2H), 7.27 (s, 1H), 6.62-6.60 (d, J=8.0 Hz, 1H), 1.24
(s, 9H). MS (M+1): 450.44. (LCMS Purity 98.83%, Rt=5.60 min)
(1).
[0420] The following compounds were made in essentially the same
manner using the appropriate ethyl ester in the first step.
TABLE-US-00015 LCMS Purity CPD. Structure (M + 1) (LCMS) .sup.1H
NMR 157 ##STR00392## 432.11 99.35% Rt = 5.36 min (1) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 8.65-8.64 (d, J = 8 Hz, 1H), 8.19-8.17
(d, J = 7.6 Hz, 1H), 7.91-7.88 (t, J = 6.8 Hz, 1H), 7.77-7.74 (d, J
= 8.4 Hz, 2H), 7.48-7.46 (m, 3H) 7.40- 7.37 (m, 1H), 6.89 (s, 1H),
6.40-6.38 (d, J = 8.4 Hz, 1H), 1.23 (s, 9H). 158 ##STR00393##
449.28 99.00% Rt = 6.87 min (2) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 7.87-7.85 (d, J = 8.4 Hz, 2H), 7.77-7.75 (d, J = 8.4 Hz,
1H), 7.57-7.55 (d, J = 8.4 Hz, 2H), 6.97 (s, 1H), 6.74- 6.72 (d, J
= 7.6 Hz, 1H), 6.61 (s, 1H), 4.10 (s, 3H), 2.18 (s, 3H), 1.24 (s,
9H). 159 ##STR00394## 434.27 94.42% Rt = 7.04 min (2) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 7.91-7.90 (d, J = 7.2 Hz, 2H),
7.68-7.64 (m, 1H), 7.59-7.57 (d, J = 8.0 Hz, 2H), 7.42-7.41 (d, J =
4.4 Hz, , 1H), 6.81 (m, 2H), 6.59-6.58 (m, 2H), 3.67 (s, 3H), 1.25
(s, 9H). 160 ##STR00395## 517.32 98.16% Rt = 5.87 min (1) .sup.1H
NMR (400 MHz, DMSO- d6): .delta. 11.36 (bs, 1H), 8.81 (d, J = 1.2
Hz, 1H), 8.32-8.31 (J = 2.8 Hz, 1H), 7.95 (s, 1H), 7.82-7.80 (d, J
= 8.4 Hz, 2H), 7.56-7.50 (m, 3H), 7.31 (s, 1H), 6.80-6.78 (d, J =
8.0 Hz, 1H), 3.93 (s, 3H), 1.15 (s, 9H). 161 ##STR00396## 462.17
99.84% Rt = 6.22 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
8.81 (s, 1H), 8.28 (s, 1H), 7.91 (s, 1H), 7.76-7.74 (d, J = 8.4 Hz,
2H), 7.48-7.46 (m, 3H), 7.05 (s, 1H), 6.39- 6.37 (d, J = 8.4 Hz,
1H), 3.94 (s, 3H), 1.25 (s, 9H).
Example 20
Synthesis of Compound 162
[4-(tert-butyl)-N-(4-chloro-2-(pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-7-yl-
)benzenesulfonamide]
##STR00397##
[0422] Synthesis of XC:
[0423] A stirred solution of compound LXV (0.5 g; 1.24 mmol) and
1-(pyrimidin-5-yl)ethan-1-one (LXXXIX; 0.6 g; 2.48 mmol) in
1,4-dioxane (40 ml) was purged with argon gas for 20 minutes. To
the reaction mixture was added
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.57 g, 0.992
mmol), palladium(II)acetate (0.11 g, 0.5 mmol) and potassium
phosphate (0.73 g, 3.47 mmol). The resultant solution was stirred
at 100.degree. C. for 15 h. The reaction mixture was cooled,
concentrated, and filtered through a celite bed. The crude reaction
mass was diluted with water and extracted with ethyl acetate. The
organic layer was washed with brine solution and dried over
anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced
pressure followed by trituration with hexane to obtain crude
4-(tert-butyl)-N-(5-chloro-6-(2-oxo-2-(pyrimidin-5-yl)ethyl)pyridin-2-yl)-
benzene sulfonamide XC, as a keto-enol tautomeric mixture. MS
(M+1): 445.2.
[0424] Synthesis of XCI:
[0425] To a stirred solution of compound XC (1.5 g, tautomeric
mixture) in methanol (60 ml) was added hydroxylamine hydrochloride
(0.93 g; 13.51 mmol) followed by a 10% aqueous solution of sodium
hydroxide (193 ml). The resultant suspension was heated at
95.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and was evaporated under reduced
pressure to obtain crude compound, which was purified by column
chromatography using 18% ethyl acetate in hexane to afford the
desired product
(4-(tert-butyl)-N-(5-chloro-6-(2-(hydroxyimino)-2-(pyrimidin-5-yl-
)ethyl)pyridin-2-yl)benzenesulfonamide as an off white solid (XCI;
0.35 g; 23% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.90
(s, 1H), 11.03 (bs, 1H), 9.11 (s, 1H), 8.95-8.87 (m, 2H), 7.73-7.69
(m, 3H), 7.53-7.48 (m, 2H), 6.82-6.80 (d, J=8.4 Hz, 1H), 4.26 (s,
2H), 1.26 (s, 9H), MS (M+1): 460.1
Synthesis of Compound 162:
4-(tert-butyl)-N-(4-chloro-2-(pyrimidin-5-yl)pyrazolo[1,5-a]pyridin-7-yl)-
benzenesulfonamide
[0426] To a stirred solution of compound XCI (0.3 g, 0.65 mmol) in
1,2-dimethoxyethane (10 ml) at 0.degree. C. was added
trifluoroacetic anhydride (0.27 g, 1.3 mmol). The reaction mixture
was allowed to stir at 0.degree. C. for 20 minutes, followed by
dropwise addition of triethylamine (0.66 g, 6.5 mmol) in
1,2-dimethoxyethane (2 ml). The reaction mixture was stirred at
room temperature for 3 h resulting in the generation of XCII in
situ. To the reaction mixture was further added iron (II) chloride
(0.033 g, 0.26 mmol) and this was then heated at 100.degree. C. for
2 h. The reaction mixture was cooled and concentrated, diluted with
water and extracted with ethyl acetate. The organic layer was
washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by column chromatography
using 30% ethyl acetate in hexane to afford the title compound as
an off white solid (162; 0.06 g; 20% yield). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 11.36 (bs, 1H), 9.34 (s, 2H), 9.21 (s, 1H),
7.80-7.78 (d, J=8.4 Hz, 2H), 7.52-7.50 (d, J=8.4 Hz, 2H), 7.47-7.45
(d, J=8.0 Hz, 1H), 7.43 (s, 1H), 6.91-6.89 (d, J=8.4 Hz, 1H), 1.14
(s, 9H). MS (M+1): 442.37 (LCMS Purity 98.93%, Rt=6.18 min)
(1).
Example 21
Synthesis of Compound 163
[N-(4-bromo-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-butyl-
)benzenesulfonamide]; Compound 164
[4-(tert-butyl)-N-(4-cyano-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-7-yl-
)benzenesulfonamide] and Compounds 165 to 166
##STR00398## ##STR00399##
[0428] Synthesis of XCIV:
[0429] To a stirred solution of compound LXXXI (2 g; 5.23 mmol) and
ethyl 1-trityl-1H-pyrazole-4-carboxylate (XCIII; 2.59 g; 6.8 mmol)
in THF (50 ml) was added sodium bis(trimethylsilyl)amide (15.7 ml,
1.0 M in THF, 15.7 mmol) drop wise at 0.degree. C. Upon complete
addition, the resultant solution was stirred at ambient temperature
for 3 h. The reaction mixture was diluted with a saturated solution
of ammonium chloride and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain
N-(5-bromo-6-(2-oxo-2-(1-trityl-1H-pyrazol-4-yl)ethyl)pyridin-2-yl)-4-(te-
rt-butyl)benzenesulfonamide XCIV, as a keto-enol tautomeric
mixture. MS (M+1): 719.12. The crude was carried forward to next
step without purification.
[0430] Synthesis of XCV:
[0431] To a stirred solution of compound XCIV (6.5 g, tautomeric
mixture) in methanol (300 ml) was added hydroxylamine hydrochloride
(3.13 g; 45.15 mmol) followed by a 10% aqueous solution of sodium
hydroxide (40 ml). The resultant suspension was heated at
100.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and was evaporated under reduced
pressure to obtain the desired product
(N-(5-bromo-6-(2-(hydroxyimino)-2-(1-trityl-1H-pyrazol-4-yl)ethyl)pyridin-
-2-yl)-4-(tert-butyl)benzenesulfonamide as an off white solid (XCV;
3 g; 45% yield). MS (M+1): 734.11 (LCMS Purity 93.21%).
[0432] Synthesis of XCVII:
[0433] To a stirred solution of compound XCV (1 g, 1.36 mmol) in
1,2-dimethoxyethane (20 ml) at 0.degree. C. was added
trifluoroacetic anhydride (0.57 g, 2.72 mmol). The reaction mixture
was allowed to stir at 0.degree. C. for 20 minutes, followed by
dropwise addition of triethylamine (1.37 g, 13.6 mmol) in
1,2-dimethoxyethane (5 ml). The reaction mixture was stirred at
room temperature for 1 h to leave XCVI in situ. To the reaction
mixture was further added iron (II) chloride (0.068 g, 0.54 mmol)
and heated at 100.degree. C. for 3 h. The reaction mixture was
cooled and concentrated, diluted with water and extracted with
ethyl acetate. The organic layer was washed with brine solution and
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude compound, which was purified
by column chromatography using 5% ethyl acetate in hexane to afford
N-(4-bromo-2-(1-trityl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(te-
rt-butyl)benzene sulfonamide as off white solid (XCVII; 0.5 g; 51%
yield). MS (M+1): 716.1.
Synthesis of Compound 163;
N-(4-bromo-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-butyl)-
benzenesulfonamide
[0434] To a stirred solution of compound XCVII, (0.5 g, 0.69 mmol)
in water (5 ml) was added trifluoroacetic acid (2 ml) at 0.degree.
C. and stirred for 5 h. The reaction mixture was diluted with water
and extracted with dichloromethane. The organic layer was washed
with brine solution, saturated aqueous sodium bicarbonate and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain crude compound, which was triturated
with diethyl ether to afford the title compound (163; 0.25 g, 75%
yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.07 (bs, 1H),
8.22-8.12 (m, 2H), 7.86-7.83 (d, J=8.8 Hz, 2H), 7.56-7.54 (d, J=8.4
Hz, 2H), 7.46-7.44 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 6.63-6.61 (d,
J=7.6 Hz, 1H), 1.20 (s, 9H). MS (M+1): 476.14. (LCMS Purity 97.60%,
Rt=4.48 min) (2).
Synthesis of Compound 164;
4-(tert-butyl)-N-(4-cyano-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-7-yl)-
benzenesulfonamide
[0435] To a stirred solution of compound 163, (0.2 g, 0.42 mmol) in
dimethylacetamide (5 ml) was added Zn(CN).sub.2 (0.15 g, 0.84
mmol). The reaction vessel and mixture was purged with argon for 20
minutes. To the reaction mixture further added 1, 1'-Bis
(diphenylphosphino)ferrocene (0.047 g, 0.084 mmol),
Pd.sub.2dba.sub.3 (0.058 g, 0.063 mmol) and a catalytic amount of
Zn dust. The reaction mixture was heated at 120.degree. C. for 3 h
in a microwave reactor. The reaction mixture was cooled, filtered
through a celite bed. The collected filtrate was concentrated,
diluted with water and extracted with dichloromethane. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by column chromatography
using 2% methanol in 1% ammoniated dichloromethane to afford the
title compound (164; 0.05 g, 28% yield). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 13.08 (bs, 1H), 8.13 (m, 2H), 7.75-7.73 (d, J=8.0
Hz, 2H), 7.48-7.46 (d, J=7.6 Hz, 2H), 7.42-7.40 (d, J=8.0 Hz, 1H),
6.65 (s, 1H), 6.35-6.33 (d, J=8.8 Hz, 1H), 1.25 (s, 9H). MS (M+1):
421.24. (LCMS Purity 98.04%, Rt=6.39) (2).
[0436] The following compounds were prepared in an essentially
similar manner using ethyl 1-methyl-1H-pyrazole-4-carboxylate
instead of ethyl 1-trityl-1H-pyrazole-4-carboxylate in the first
step. No deprotection chemistry is necessary.
TABLE-US-00016 LCMS Purity CPD. Structure (M + 1) (LCMS) .sup.1H
NMR 165 ##STR00400## 490.11 96.47% Rt = 4.73 min (2) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 8.17 (s, 1H), 7.87-7.83 (m, 3H),
7.57-7.55 (d, J = 8.0 Hz, 2H), 7.46-7.44 (d, J = 8.0 Hz, 1H), 6.80
(s, 1H), 6.63- 6.61 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 1.20 (s,
9H). 166 ##STR00401## 435.48 98.90% Rt = 5.29 min (1) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 8.26 (s, 1H), 7.91 (s, 1H), 7.73-7.71
(d, J = 8.0 Hz, 2H), 7.46-7.44 (d, J = 8.0 Hz, 2H), 7.39-7.37 (d, J
= 8.4 Hz, 1H), 6.57 (s, 1H), 6.32-6.30 (d, J = 8.4 Hz, 1H), 3.87
(s, 3H), 1.25 (s, 9H).
Example 22
Synthesis of Compound 167
[4-(tert-butyl)-N-(4-chloro-2-(1-methyl-1H-pyrrol-3-yl)pyrazolo[1,5-a]pyr-
i dine-7-yl)benzenesulfonamide]
##STR00402##
[0438] Synthesis of XCIX:
[0439] To a stirred solution of compound LXXIX (2 g; 5.90 mmol) and
N-methoxy-N, 1-dimethyl-1H-pyrrole-3-carboxamide (XCVIII; 1.48 g;
8.85 mmol) in THF (50 ml) was added sodium bis(trimethylsilyl)amide
(47 ml, 1.0 M in THF, 47 mmol) dropwise at 0.degree. C. Upon
complete addition, the resultant solution was stirred at ambient
temperature for 2 h. The reaction mixture was diluted with a
saturated solution of ammonium chloride and extracted with ethyl
acetate. The organic layer was washed with brine solution and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain
4-(tert-butyl)-N-(5-chloro-6-(2-(1-methyl-1H-pyrrol-3-yl)-2-oxoethyl)pyri-
din-2-yl)benzenesulfonamide XCIX, as a keto-enol tautomeric
mixture. MS (M+1): 446.12. The crude material was carried forward
to next step without purification.
[0440] Synthesis of C:
[0441] To a stirred solution of compound XCIX (3 g, tautomeric
mixture) in methanol (80 ml) was added hydroxylamine hydrochloride
(2.3 g; 33.62 mmol) followed by a 10% aqueous solution of sodium
hydroxide (10 ml). The resultant suspension was heated at
100.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by column chromatography
using 25% ethyl acetate in hexane to afford the desired product
4-(tert-butyl)-N-(5-chloro-6-(2-(hydroxyimino)-2-(1-methyl-1H-pyr-
rol-3-yl)ethyl)pyridin-2-yl)benzenesulfonamide as an off white
solid (C; 0.7 g; 23% yield). MS (M+1): 461.1 (LCMS Purity 99%).
Synthesis of Compound 167;
4-(tert-butyl)-N-(4-chloro-2-(1-methyl-1H-pyrrol-3-yl)pyrazolo[1,5-a]pyri-
dine-7-yl)benzenesulfonamide
[0442] To a stirred solution of C (0.6 g, 1.30 mmol) in
1,2-dimethoxyethane (12 ml) at 0.degree. C. was added
trifluoroacetic anhydride (0.54 g, 2.60 mmol). The reaction mixture
was allowed to stir at 0.degree. C. for 20 minutes, followed by
dropwise addition of triethylamine (1.31 g, 13.0 mmol) in
1,2-dimethoxyethane (2 ml). The reaction mixture was stirred at
room temperature for 3 h to form CI in situ. To the reaction
mixture was further added iron (II) chloride (0.065 g, 0.52 mmol)
and the mixture heated at 100.degree. C. for 2 h. The reaction
mixture was cooled and concentrated, diluted with water and
extracted with ethyl acetate. The organic layer was washed with
brine solution and dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to obtain crude compound,
which was purified by column chromatography using 20% ethyl acetate
in hexane to afford the title compound as an off white solid (167;
0.02 g). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.88-8.86 (d,
J=8.0 Hz, 2H), 7.57-7.55 (d, J=8.0 Hz, 2H), 7.28-7.26 (d. J=8.0 Hz,
2H), 6.75-6.72 (d, J=12.4 Hz, 2H), 6.61-6.59 (d, J=8 Hz, 1H), 6.47
(s, 1H), 3.66 (s, 3H), 1.21 (s, 9H). MS (M+1): 443.19 (LCMS Purity
94.12%, Rt=5.12 min) (2).
Example 23
Synthesis of Compound 168
[4-(tert-butyl)-N-(4-chloro-2-(thiazol-5-yl)pyrazolo[1,5-a]pyridin-7-yl)b-
enzenesulfonamide]
##STR00403##
[0444] Synthesis of CIII:
[0445] To a stirred solution of compound LXXIX (1.5 g; 4.43 mmol)
in THF (20 ml) was added n-butyl lithium (14 ml, 1.6M in hexane,
22.15 mmol) dropwise at -78.degree. C. After stirring for 15 min,
N-methoxy-N-methylthiazole-5-carboxamide (CII, 1.28 g; 13.3 mmol)
in THF was added. The resultant solution was stirred at ambient
temperature for 15 min. The reaction mixture was diluted with a
saturated solution of ammonium chloride and extracted with ethyl
acetate. The organic layer was washed with brine solution and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain
4-(tert-butyl)-N-(5-chloro-6-(2-oxo-2-(thiazol-5-yl)ethyl)pyridin-2-yl)be-
nzenesulfonamide CIII, as a keto-enol tautomeric mixture. MS (M+1):
450.2. The crude was carried forward to next step without
purification.
[0446] Synthesis of CIV:
[0447] To a stirred solution of compound CIII (2.2 g, tautomeric
mixture) in methanol (20 ml) was added hydroxylamine hydrate (1.05
g; 14.69 mmol) followed by a 10% aqueous solution of sodium
hydroxide (15 ml). The resultant suspension was heated at
100.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by column chromatography
using 30% ethyl acetate in hexane to afford desired product
4-(tert-butyl)-N-(5-chloro-6-(2-(hydroxyimino)-2-(thiazol-5-yl)et-
hyl)pyridin-2-yl)benzenesulfonamide as an off white solid (CIV; 1.2
g; 53% yield). MS (M+1): 465.12.
Synthesis of Compound 168;
4-(tert-butyl)-N-(4-chloro-2-(thiazol-5-yl)pyrazolo[1,5-a]pyridin-7-yl)be-
nzenesulfonamide
[0448] To a stirred solution of compound CIV (0.5 g, 1.07 mmol) in
1,2-dimethoxyethane (12 ml) at 0.degree. C. was added
trifluoroacetic anhydride (0.18 g, 0.86 mmol). The reaction mixture
was allowed to stir at 0.degree. C. for 20 minutes and
triethylamine (0.54 g, 5.35 mmol) in 1,2-dimethoxyethane (2 ml) was
added in dropwise fashion. The reaction mixture was stirred at room
temperature for 3 h leading to the preparation of Compound CV in
situ. To the reaction mixture was further added iron (II) chloride
(0.054 g, 0.42 mmol) and the resulting suspension was heated at
100.degree. C. for 2 h. The reaction mixture was cooled and
concentrated, diluted with water and extracted with ethyl acetate.
The organic layer was washed with brine solution and dried over
anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced
pressure to obtain crude compound, which was purified by column
chromatography using 35% ethyl acetate in hexane to afford the
title compound as an off white solid (168; 0.04 g). .sup.1H NMR
(400 MHz, DMSO-d6): .delta. 11.32 (bs, 1H), 9.14 (s, 1H), 8.48 (s,
1H), 7.78-7.76 (d, J=8.4 Hz, 2H), 7.50-7.48 (d, J=7.2 Hz, 2H), 7.35
(m, 1H), 7.13 (s, 1H), 6.66 (m, 1H), 1.18 (s, 9H). MS (M+1): 447.37
(LCMS Purity 96.76%, Rt=5.75 min) (1).
Example 24
Synthesis of Compound 169
[4-(tert-butyl)-N-(4-chloro-2-(oxazol-5-yl)pyrazolo[1,5-a]pyridin-7-yl)be-
nzenesulfonamide]; and Compound 170
[4-(tert-butyl)-N-(4-cyano-2-(oxazol-5-yl)pyrazolo[1,5-a]pyridin-7-yl)ben-
zenesulfonamide]
##STR00404##
[0450] Synthesis of CVII:
[0451] To a stirred solution of compound LXXIX (1.7 g; 5.02 mmol)
and ethyl 2-(triisopropylsilyl)oxazole-5-carboxylate (CVI; 5.9 g;
20.11 mmol) in THF (25 ml) was added sodium
bis(trimethylsilyl)amide (50 m, 1.0 M in THF, 50 mmol) dropwise at
0.degree. C. The resultant solution was stirred at ambient
temperature for 3 h. The reaction mixture was diluted with a
saturated solution of ammonium chloride and extracted with ethyl
acetate. The organic layer was washed with brine solution and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain
4-(tert-butyl)-N-(5-chloro-6-(2-oxo-2-(2-(triisopropylsilyl)oxazol-
-5-yl)ethyl)pyridin-2-yl)benzenesulfon amide CVII, as a keto-enol
tautomeric mixture. MS (M+1): 590.2. The crude material was carried
forward to next step without purification.
[0452] Synthesis of CVIII:
[0453] To a stirred solution of compound CVII (3.2 g, tautomeric
mixture) in methanol (26 ml) was added hydroxylamine hydrate (0.53
g; 16.29 mmol) followed by a 10% aqueous solution of sodium
hydroxide (30 ml). The resultant suspension was heated at
100.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and was evaporated under reduced
pressure to obtain crude compound, which was purified by column
chromatography using 30% ethyl acetate in hexane to afford the
desired product
4-(tert-butyl)-N-(5-chloro-6-(2-(hydroxyimino)-2-(2-(triisopropyl-
silyl) oxazol-5-yl)ethyl)pyridin-2-yl)benzenesulfonamide as an off
white solid (CVIII; 0.3 g; 9% yield. MS (M+1): 605.12.
Synthesis of Compound 169;
4-(tert-butyl)-N-(4-chloro-2-(oxazol-5-yl)pyrazolo[1,5-a]pyridin-7-yl)ben-
zene sulfonamide
[0454] To a stirred solution of CVIII (0.3 g, 0.49 mmol) in
1,2-dimethoxyethane (12 ml) at 0.degree. C. was added
trifluoroacetic anhydride (0.082 g, 0.39 mmol). The reaction
mixture was allowed to stir at 0.degree. C. for 20 minutes,
followed by dropwise addition of triethylamine (0.24 g, 2.45 mmol)
in 1,2-dimethoxyethane (2 ml). The reaction mixture was stirred at
room temperature for 3 h to prepare CIX in situ. To the reaction
mixture further added iron (II) chloride (0.024 g, 0.19 mmol) and
this was heated at 100.degree. C. for 2 h. The reaction mixture was
cooled and concentrated, diluted with water and extracted with
ethyl acetate. The organic layer was washed with brine solution and
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude compound, which was purified
by column chromatography using 30% ethyl acetate in hexane to
afford the title compound as an off white solid (169; 0.05 g; 23%
yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.55 (s, 1H),
7.82-7.80 (d, J=8.4 Hz, 2H), 7.68 (s, 1H), 7.54-7.52 (d, J=8.4 Hz,
2H), 7.45-7.43 (d, J=7.6 Hz, 1H), 7.04 (s, 1H), 6.78-6.76 (d, J=8.0
Hz, 1H), 1.19 (s, 9H). MS (M+1): 431.35 (LCMS Purity 97.44%,
Rt=5.67 min) (1).
Synthesis of Compound 170;
4-(tert-butyl)-N-(4-cyano-2-(oxazol-5-yl)pyrazolo[1,5-a]pyridin-7-yl)benz-
ene sulfonamide
[0455] To a stirred solution of compound 169, (0.07 g, 0.16 mmol)
in dimethylacetamide (5 ml) was added Zn(CN).sub.2 (0.025 g, 0.20
mmol). The reaction mixture was purged with argon for 20 min. To
the reaction mixture was further added 1,1'-Bis
(diphenylphosphino)ferrocene (0.08 g, 0.14 mmol), Pd.sub.2dba.sub.3
(0.12 g, 0.14 mmol) and a catalytic amount of Zn dust. The reaction
mixture was heated at 120.degree. C. for 2 h in a microwave
reactor. The reaction mixture was cooled and filtered through a
celite bed. The filtrate was concentrated, diluted with water and
extracted with dichloromethane. The organic layer was washed with
brine solution and dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to obtain the crude compound,
which was purified by column chromatography using 2% methanol in
dichloromethane to afford the title compound (170; 0.013 g, 20%
yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.50 (s, 1H),
7.76-7.72 (m, 3H), 7.50-7.46 (m, 3H), 6.72 (s, 1H), 6.43-6.41 (d,
J=8.0 Hz, 1H), 1.25 (s, 9H). MS (M+1): 422.46 (LCMS Purity 99.60%,
Rt=5.16 min) (1).
Example 25
Synthesis of Compound 171 [methyl
3-(7-((4-(tert-butyl)phenyl)sulfonamido)-4-chloropyrazolo[1,5-a]pyridin-2-
-yl)thiophene-2-carboxylate] and Compound 172
[3-(7-((4-(tert-butyl)phenyl)sulfonamido)-4-chloropyrazolo[1,5-a]pyridin--
2-yl)thiophene-2-carboxylic acid]
##STR00405##
[0457] Synthesis of CXI:
[0458] A stirred solution of compound LXV (1 g, 2.48 mmol) in
dimethylformide (40 ml) was placed in a sealed tube which was
purged with argon for 20 minutes. To the reaction mixture was added
Bis(triphenylphosphine)palladium(II) chloride (0.26 g, 0.37 mmol),
copper(I)iodide (0.07 g, 0.37 mmol) and triethylamine (0.72 g, 7.19
mmol). The reaction mixture was cooled to 0.degree. C., followed by
addition of methyl 3-ethynylthiophene-2-carboxylate (CX; 2 g, 12.0
mmol). The reaction mixture was re-sealed and heated at 100.degree.
C. for 24 h. The reaction mixture was cooled and filtered through a
celite bed. The collected filtrate was concentrated, diluted with
water and extracted with ethyl acetate. The organic layer was
washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound CXI, methyl
3-((6-((4-(tert-butyl)phenyl)sulfonamido)-3-chloropyridin-2-yl)ethynyl)th-
iophene-2-carboxylate. MS (M+1): 489.16.
[0459] Synthesis of CXII:
[0460] To a stirred solution of CXI (0.2 g, 0.41 mmol) in
dichloromethane (5 ml) was added O-(mesitylsulfonyl) hydroxylamine
(LXII; 1 g). The reaction mixture was stirred for 24 h at room
temperature, diluted with water and extracted with dichloromethane
which was washed with a saturated aqueous solution of sodium
bicarbonate. The organic layer was further washed with brine
solution, dried over anhydrous Na.sub.2SO.sub.4, filtered and
evaporated under reduced pressure to obtain crude compound CXII,
1-amino-6-((4-(tert-butyl)phenyl)sulfonamido)-3-chloro-2-((2-(methoxycarb-
onyl)thiophen-3-yl)ethynyl)pyridin-1-ium
2,4,0-trimethylbenzenesulfonate. MS (M+1): 505.12. The crude
material was carried forward to next step without purification.
Synthesis of Compound 171: methyl
3-(7-((4-(tert-butyl)phenyl)sulfonamido)-4-chloropyrazolo[1,5-a]pyridin-2-
-yl)thiophene-2-carboxylate
[0461] To a stirred solution of CXII (0.2 g, crude) in
dimethylformide (3 ml) was added potassium carbonate (0.27 g, 1.98
mmol). The reaction mixture was stirred at 60.degree. C. for 1 h.
The reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by preparative HPLC to
afford the title compound (171; 0.019 g). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 11.34 (bs, 1H), 7.97-7.96 (d, J=5.2 Hz, 1H),
7.82-7.80 (d, J=8.8 Hz, 2H), 7.70-7.69 (d, J=5.2 Hz, 1H), 7.54-7.52
(d, J=8.4 Hz, 2H), 7.42-7.40 (m, 2H), 6.84-6.82 (d, J=8.4 Hz, 1H),
3.81 (s, 3H), 1.19 (s, 9H). MS (M+1): 504.12. (LCMS Purity 97.74%,
Rt=5.34 min) (2).
Synthesis of Compound 172;
3-(7-((4-(tert-butyl)phenyl)sulfonamido)-4-chloropyrazolo[1,5-a]pyridin-2-
-yl)thiophene-2-carboxylic acid
[0462] To a stirred solution of 171 (0.09 g, 0.17 mmol) in a
mixture of methanol, tetrahydrofuran and water (1:1:0.5) (2.5 ml)
was added lithium hydroxide (0.013 g, 0.53 mmol). The reaction
mixture was stirred at room temperature for 12 h. This was
concentrated under reduced pressure, diluted with water and
acidified with an aqueous solution of potassium bisulphate to pH
1-2. The aqueous layer was extracted with ethyl acetate, which was
washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4,
filtered and evaporated under reduced pressure to afford the title
compound as an off white solid (172; 0.021 g; 20% yield). .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 7.90-7.89 (d, J=4.8 Hz, 1H),
7.82-7.80 (d, J=8.4 Hz, 2H), 7.69-7.68 (d, J=5.2 Hz, 1H), 7.53-7.51
(d, J=8.8 Hz, 2H), 7.40-7.38 (m, 2H), 6.81-6.79 (d, J=8.0 Hz, 1H),
1.19 (s, 9H). MS (M+1): 490.11. (LCMS Purity 98.97%, Rt=6.90 min)
(2).
Example 26
Synthesis of Compound 173
[4-(tert-butyl)-N-(4-methoxy-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-
benzenesulfonamide]; and Compounds 174-175
##STR00406##
[0464] Synthesis of CXIV:
[0465] To a stirred solution of compound CXIII (0.38 g, 2.75 mmol)
in chloroform (2 ml) was added pyridine (7.6 ml) at 0.degree. C.
followed by addition of 4-tert-butylbenzenesulfonyl chloride (XI,
0.76 g, 3.3 mmol). The reaction mixture was heated at 100.degree.
C. for 12 h and then cooled to room temperature and concentrated
under reduced pressure. The crude mass was diluted with a saturated
ammonium chloride solution and extracted with ethyl acetate. The
organic layer was washed with brine solution, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford
4-(tert-butyl)-N-(5-methoxy-6-methylpyridin-2-yl)benzenesulfonamide
(CXIV; 0.89 g, 97% yield). .sup.1H NMR (400 MHz, CDCl3): .delta.
7.75-7.73 (d, J=8.4 Hz, 2H), 7.44-7.42 (d, J=8.4 Hz, 2H), 7.24 (m,
1H), 7.09-7.07 (d, J=8.4 Hz, 1H), 3.78 (s, 3H), 2.28 (s, 3H), 1.29
(s, 9H). MS (M+1): 335.2.
[0466] Synthesis of CXV:
[0467] To a stirred solution of compound CXIV (0.89 g; 2.66 mmol)
and ethyl nicotinate (LXX; 0.44 g; 2.92 mmol) in THF (30 ml) was
added sodium bis(trimethylsilyl)amide (8 ml, 1.0 M in THF, 7.98
mmol) dropwise at 0.degree. C. The resultant solution was stirred
at ambient temperature for 3 h.
[0468] The reaction mixture was diluted with a saturated solution
of ammonium chloride and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain
4-(tert-butyl)-N-(5-methoxy-6-(2-oxo-2-(pyridin-3-yl)ethyl)pyridin-2-yl)b-
enzenesulfonamide CXV, as a keto-enol tautomeric mixture. MS (M+1):
440.2. The crude material was carried forward to next step without
purification.
[0469] Synthesis of CXVI:
[0470] To a stirred solution of compound 275 (1 g, tautomeric
mixture) in methanol (100 ml) was added hydroxylamine hydrochloride
(0.79 g; 11.38 mmol) followed by a 10% aqueous solution of sodium
hydroxide (10 ml). The resultant suspension was heated at
100.degree. C. for 12 h. The reaction mixture was cooled and
concentrated in vacuo. The residue was diluted with water and
extracted with ethyl acetate. The organic layer was washed with
brine solution and dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to obtain crude compound,
which was purified by column chromatography using 60% ethyl acetate
in hexane to afford desired product
4-(tert-butyl)-N-(6-(2-(hydroxyimino)-2-(pyridin-3-yl)ethyl)-5-methoxypyr-
idin-2-yl)benzene sulfonamide as off white solid (CXVI; 0.8 g; 79%
yield). MS (M+1): 455.1.
Synthesis of 173;
4-(tert-butyl)-N-(4-methoxy-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)b-
enzenesulfonamide
[0471] To a stirred solution of CXVI (0.82 g, 1.80 mmol) in
1,2-dimethoxyethane (15 ml) at 0.degree. C. was added
trifluoroacetic anhydride (0.75 g, 3.6 mmol). The reaction mixture
was allowed to stir at 0.degree. C. for 20 minutes, followed by
dropwise addition of triethylamine (0.91 g, 9 mmol) in
1,2-dimethoxyethane (2 ml). The reaction mixture was stirred at
room temperature for 2 h to leave CXVII in situ. To the reaction
mixture was further added iron (II) chloride (0.09 g, 0.72 mmol)
and this was heated at 90.degree. C. for 2 h. The reaction mixture
was cooled, concentrated, diluted with water and extracted with
ethyl acetate. The organic layer was washed with brine solution and
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude compound, which was purified
by column chromatography using 30% ethyl acetate in hexane to
afford the title compound as off white solid (173; 0.04 g). .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 10.74 (bs, 1H), 8.99 (d, J=1.6 Hz,
1H), 8.54-8.53 (m, 1H), 8.16-8.14 (d, J=7.6 Hz, 1H), 7.65-7.62 (d,
J=8.4 Hz, 2H), 7.46-7.39 (m, 3H), 7.17 (s, 1H), 6.79-6.77 (d, J=8
Hz, 1H), 6.69-6.67 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 1.05 (s, 9H) MS
(M+1): 437.39. (LCMS Purity 97.17%, Rt=5.95 min) (1).
[0472] The following compounds were prepared in a similar manner
using the appropriate sulfonyl chloride.
TABLE-US-00017 LCMS Purity CPD Structure (M + 1) (LCMS) .sup.1H NMR
174 ##STR00407## 449.13 96.03%, Rt = 5.04 min (1) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 11.16 (bs, 1H), 8.93- 8.93 (d, J = 1.2 Hz,
1H), 8.53- 8.53 (d, J = 3.6 Hz, 1H), 7.98- 7.96 (d, J = 8.4 Hz,
1H), 7.93- 7.91 (d, J = 8.0 Hz, 2H), 7.81- 7.79 (d, J = 8.4, 2H),
7.41- 7.38 (m, 1H), 7.20 (s, 1H), 6.83-6.81 (d, J = 8.0 Hz, 1H),
6.70-6.68 (d, J = 8.0 Hz 1H), 3.95 (s, 3H) 175 ##STR00408## 483.06
97.45%, Rt = 5.53 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
11.28 (bs, 1H), 9.02 (s, 1H), 8.63 (m, 1H), 8.12 (m, 1H), 8.00-7.97
(m, 2H), 7.79 (m, 1H), 7.56 (m, 1H), 7.28 (s, 1H), 6.89 (m, 1H),
6.73 (m, 1H), 3.96 (s, 3H).
Example 27
Synthesis of Compound 176
[N-(4-bromo-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-butyl)be-
nzenesulfonamide]; and Compound 177
[4-(tert-butyl)-N-(4-(methylsulfonyl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyri-
din-7-yl)benzenesulfonamide]
##STR00409## ##STR00410##
[0474] Synthesis of CXVIII:
[0475] To a stirred solution of compound LXXXI (5 g; 13.08 mmol)
and ethyl nicotinate (LXX; 5.96 g; 39.24 mmol) in THF (60 ml) was
added sodium bis(trimethylsilyl)amide (59 ml, 1.0 M in THF, 58.86
mmol) dropwise at 0.degree. C. Upon complete addition, the
resultant solution was stirred at ambient temperature for 6 h. The
reaction mixture was diluted with a saturated solution of ammonium
chloride and extracted with ethyl acetate. The organic layer was
washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain CXVIII,
N-(5-bromo-6-(2-oxo-2-(pyridin-3-yl)ethyl)pyridin-2-yl)-4-(tert-butyl)ben-
zene sulfonamide as a keto-enol tautomeric mixture. MS (M+1):488.2.
The crude material was carried forward to next step without
purification.
[0476] Synthesis of CXIX:
[0477] To a stirred solution of compound CXVIII (15 g, tautomeric
mixture) in methanol (100 ml) was added hydroxylamine hydrochloride
(15 g; 215 mmol) followed by a 10% aqueous solution of sodium
hydroxide (40 ml). The resultant suspension was heated at
90.degree. C. for 10 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by column chromatography
using 40% ethyl acetate in hexane to afford the desired product
N-(5-bromo-6-(2-(hydroxyimino)-2-(pyridin-3-yl)ethyl)pyridin-2-yl)-4-(ter-
t-butyl)benzenesulfonamide (CXIX; 9 g; 58% yield). .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.64 (s, 1H), 11.03 (bs, 1H), 8.66 (s, 1H),
8.47-8.46 (d, J=3.6 Hz, 1H), 7.82-7.74 (m, 4H), 7.50-7.47 (d, J=8.8
Hz, 2H), 7.28-7.25 (m, 1H), 6.72-6.70 (d, J=8.4 Hz, 1H), 4.23 (s,
2H), 1.25 (s, 9H). MS (M+1): 505.32 (LCMS Purity 95.64%).
Synthesis of Compound 176;
N-(4-bromo-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-butyl)ben-
zenesulfonamide
[0478] To a stirred solution of compound CXIX (1 g, 1.99 mmol) in
1,2-dimethoxyethane (15 ml) at 0.degree. C. was added
trifluoroacetic anhydride (0.83 g, 3.98 mmol). The reaction mixture
was allowed to stir at 20.degree. C. for 20 minutes, followed by
dropwise addition of triethylamine (2.01 g, 19.9 mmol) in
1,2-dimethoxyethane (10 ml). The reaction mixture was stirred at
room temperature for 2 h, forming CXX in situ. To the reaction
mixture was further added iron (II) chloride (0.1 g, 0.79 mmol) and
heated at 100.degree. C. for 2 h. The reaction mixture was cooled
and concentrated, diluted with water and extracted with ethyl
acetate. The organic layer was washed with brine solution and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain the crude compound, which was purified
by column chromatography using 25% ethyl acetate in hexane to
afford the title compound as an off white solid (176; 0.2 g; 20%
yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 11.32 (bs, 1H),
9.23 (s, 1H), 8.60-8.59 (d, J=4.8 Hz, 1H), 8.38-8.36 (d, J=8.0 Hz,
1H), 7.83-7.81 (d, J=8.4 Hz, 2H), 7.56-7.49 (m, 4H), 7.25 (s, 1H),
6.80-6.78 (d, J=8.0 Hz, 1H), 1.15 (s, 9H). MS (M+1): 487.09.1 (LCMS
Purity 99.12%, Rt=6.21 min) (2).
Synthesis of Compound 177;
4-(tert-butyl)-N-(4-(methylsulfonyl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrid-
in-7-yl)benzenesulfonamide
[0479] To a stirred solution of 176 (0.25 g, 0.51 mmol) in
dimethylsulfoxide (10 ml) was added sodium methanesulfinate (0.26
g, 2.55 mmol), copper (II) triflate (0.22 g, 0.61 mmol) and N,
N-dimethylethylene diamine (0.05 g, 0.51 mmol). The reaction
mixture was heated at 120.degree. C. for 1 h in a microwave
reactor. The reaction mixture was cooled and concentrated, diluted
with water and extracted with ethyl acetate. The organic layer was
washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain the crude compound, which was purified by preparative HPLC
to afford the title compound as an off white solid (177; 0.03 g).
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.41 (s, 1H), 8.71 (m, 2H),
7.95-7.93 (d, J=8.4 Hz, 2H), 7.75-7.69 (m, 2H), 7.60-7.58 (d, J=8.4
Hz, 2H), 7.46 (s, 1H), 6.93-6.91 (m, 1H), 3.26 (s, 3H), 1.24 (s,
9H). MS (M+1): 485.16. (LCMS Purity 99.22%, Rt=5.64 min) (2).
Example 28
Synthesis of Compound 178
[4-(tert-butyl)-N-(4-cyclopropyl-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-
-yl)benzenesulfonamidel]
##STR00411##
[0481] A stirred solution of compound 176 (0.15 g, 0.31 mmol) in
1,4-dioxane (8 ml) was purged with argon for 20 minutes, followed
by addition of cyclopropylboronic acid (0.16 g, 1.86 mmol),
[1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II),
complex with dichloromethane (0.05 g, 0.06 mmol) and potassium
carbonate (0.13 g, 0.9 mmol). The reaction mixture was heated at
120.degree. C. for 12 h. The reaction mixture was cooled and
filtered through a celite bed. The filtrate was concentrated,
diluted with water and extracted with dichloromethane. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by column chromatography
using 2% methanol in dichloromethane to afford the title compound
(178; 0.01 g). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.18 (s,
1H), 8.53-8.53 (d, J=3.6 Hz, 1H), 8.36-8.34 (d, J=7.6 Hz, 1H),
7.71-7.69 (d, J=8.4 Hz, 2H), 7.48-7.45 (m, 1H), 7.40-7.38 (d, J=8.4
Hz, 2H), 6.99 (s, 1H), 6.53-6.51 (d, J=8 Hz, 1H), 6.17-6.15 (d,
J=7.6 Hz, 1H), 1.93 (m, 1H), 1.23 (s, 9H), 0.84-0.81 (m, 2H),
0.58-0.57 (m, 2H). MS (M+1): 447.23. (LCMS Purity 96.87%, Rt=6.14
min) (2).
Example 29
Synthesis of Compound 179
[N-(6-bromo-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-butyl)be-
nzenesulfonamide] and Compound 180
[4-(tert-butyl)-N-(6-cyano-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)be-
nzenesulfonamide]
##STR00412##
[0483] Synthesis of CXXII:
[0484] To a stirred solution of compound CXXI (5 g, 26.88 mmol) in
chloroform (60 ml) was added pyridine (20 ml) at 0.degree. C.
followed by addition of 4-tert-butylbenzenesulfonyl chloride (XI,
12.4 g, 53.76 mmol). The reaction mixture was heated at 100.degree.
C. for 12 h. The reaction mixture was cooled to room temperature
and concentrated under reduced pressure. The crude mass was diluted
with saturated ammonium chloride solution and extracted with ethyl
acetate. An organic layer was washed with brine solution, dried
over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced
pressure to afford
N-(3-bromo-6-methylpyridin-2-yl)-4-(tert-butyl)benzenesulfonamide
(CXXII; 9 g, 90% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.18 (bs, 1H), 7.86-7.83 (m, 2H), 7.60-7.58 (d, J=8.4 Hz, 2H),
6.88-6.86 (d, J=8.4 Hz, 2H), 2.39 (s, 3H), 1.27 (s, 9H). MS (M+1):
381.22. (LCMS Purity 97.01%).
[0485] Synthesis of CXXIII:
[0486] To a stirred solution of compound CXXII (2.5 g; 6.53 mmol)
and ethyl nicotinate (LXX; 1.97 g; 13.05 mmol) in THF (20 ml) was
added sodium bis(trimethylsilyl)amide (35 ml, 1.0 M in THF, 32.63
mmol) dropwise at 0.degree. C. The resultant solution was stirred
at ambient temperature for 2 h. The reaction mixture was diluted
with saturated solution of ammonium chloride and extracted with
ethyl acetate. The organic layer was washed with brine solution and
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to
N-(3-bromo-6-(2-oxo-2-(pyridin-3-yl)ethyl)pyridin-2-yl)-4-(tert-butyl)ben-
zenesulfonamide CXXIII, as a keto-enol tautomeric mixture. MS
(M+1): 491.12. The crude was carried forward to next step without
purification.
[0487] Synthesis of CXXIV:
[0488] To a stirred solution of compound CXXIII (6 g, tautomeric
mixture) in methanol (120 ml) was added hydroxylamine hydrochloride
(4.28 g; 61.6 mmol) followed by a 10% aqueous solution of sodium
hydroxide (50 ml). The resultant suspension was heated at
100.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain desired product
N-(3-bromo-6-(2-(hydroxyimino)-2-(pyridin-3-yl)ethyl)pyridin-2-yl)-4-(ter-
t-butyl) benzenesulfonamide as off white solid (CXXIV; 4 g; 64%
yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.64 (bs, 1H),
11.04 (bs, 1H), 8.67 (s, 1H), 8.47-8.46 (d, J=3.6 Hz, 1H),
7.88-7.74 (m, 4H), 7.60-7.58 (d, J=8.8 Hz, 2H), 7.28-7.25 (m, 1H),
6.72-6.70 (d, J=8.4 Hz, 1H), 4.23 (s, 2H), 1.25 (s, 9H). MS (M+1):
503.23.
Synthesis of Compound 179;
N-(6-bromo-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-butyl)ben-
zenesulfonamide
[0489] To a stirred solution of compound CXXIV (1.5 g, 2.98 mmol)
in 1,2-dimethoxyethane (26 ml) at 0.degree. C. was added
trifluoroacetic anhydride (0.84 g, 5.99 mmol). The reaction mixture
was allowed to stir at 0.degree. C. for 20 minutes, followed by
drop wise addition of triethylamine (4.1 g, 2.99 mmol) in
1,2-dimethoxyethane (5 ml). The reaction mixture was stirred at
room temperature for 1 h. To the reaction mixture was further added
iron (II) chloride (0.15 g, 1.19 mmol) and the resulting mixture
heated at 100.degree. C. for 3 h. The reaction mixture was cooled
and concentrated, diluted with water and extracted with ethyl
acetate. The organic layer was washed with brine solution and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain crude compound, which was purified by
column chromatography using 21% ethyl acetate in hexane to afford
the title compound as a white solid (179; 0.5 g; 30% yield).
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.21 (s, 1H), 8.61-8.60 (d,
J=4.8 Hz, 1H), 8.40-8.38 (d, J=7.6 Hz, 1H), 7.83-7.81 (d, J=8.0 Hz,
2H), 7.57-7.51 (m, 4H), 7.27 (s, 1H), 6.81-6.79 (d, J=7.6 Hz, 1H),
1.15 (s, 9H). MS (M+1): 485.11 (LCMS purity 98.72%, Rt=6.22 min)
(2).
Synthesis of Compound 180;
4-(tert-butyl)-N-(6-cyano-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)ben-
zenesulfonamide
[0490] To a stirred solution of compound 179, (0.25 g, 0.52 mmol)
in dimethylacetamide (10 ml) was added Zn(CN).sub.2 (0.12 g, 1.03
mmol). The reaction mixture was purged with argon for 20 minutes
before 1,1'-Bis (diphenylphosphino)ferrocene (0.056 g, 0.103 mmol),
Pd.sub.2dba.sub.3 (0.094 g, 0.103 mmol) and a catalytic amount of
Zn dust were added. The reaction mixture was heated at 120.degree.
C. for 2 h in a microwave reactor. The reaction mixture was cooled
and filtered through a celite bed. The filtrate was concentrated,
diluted with water and extracted with dichloromethane. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain the crude compound, which was purified by column
chromatography using 2% methanol in 4% ammoniated dichloromethane
to
4-(tert-butyl)-N-(6-cyano-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)-
benzenesulfonamide (180; 0.08 g, 36% yield). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 8.32 (s, 1H), 8.67 (m, 1H), 8.61-8.59 (d, J=7.6
Hz, 1H), 7.84-7.82 (d, J=8.4 Hz, 2H), 7.66-7.63 (d, J=8.4 Hz, 2H),
7.54-7.51 (d, J=8.4 Hz, 2H), 7.23 (s, 1H), 6.61-6.59 (d, J=8 Hz,
1H), 1.24 (s, 9H). MS (M+1): 432.15 (LCMS purity 99.17%, Rt=5.19
min) (1).
Example 30
Synthesis of Compound 165
4-(tert-butyl)-N-(4-bromo-2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyri-
din-7-yl)benzenesulfonamide; Compound 166
4-(tert-butyl)-N-(4-cyano-2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyri-
din-7-yl)benzenesulfonamide and Compounds 181 to 193
##STR00413## ##STR00414##
[0492] Synthesis of LXXXI:
[0493] To a stirred solution of compound LXXX (200 g, 1.07 mol) in
chloroform (1 L) was added pyridine (600 ml) at 0.degree. C.
followed by addition of 4-tert-butylbenzenesulphonyl chloride (XI,
299 g, 1.28 mol). The reaction mixture was heated at 100.degree. C.
for 4 h, cooled to room temperature and concentrated under reduced
pressure. The crude mass was diluted with a saturated ammonium
chloride solution and extracted with ethyl acetate. The organic
layer was washed with brine solution, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford
N-(5-bromo-6-methylpyridin-2-yl)-4-(tert-butyl)benzenesulfonamide
(LXXXI, 320 g, 78% yield). H NMR (400 MHz, DMSO-d6) .delta. 11.14
(bs, 1H), 7.86-7.82 (m, 3H), 7.60-7.58 (d, J=8.4 Hz, 2H), 6.87-6.85
(d, J=10.4 Hz, 1H), 2.39 (s, 3H), 1.27 (s, 9H). MS (M+1):
383.2.
[0494] Synthesis of CXXV:
[0495] To a stirred solution of compound LXXXI (250 g; 0.65 mol)
and ethyl 1-methyl-1H-pyrazole-4-carboxylate (LI; 151 g; 0.98 mol)
in THF (500 ml) was added sodium bis(trimethylsilyl)amide (2.6 L,
1.0 M in THF, 2.61 mol) dropwise at 0.degree. C. Upon complete
addition, the resultant solution was stirred at ambient temperature
for 12 h. The reaction mixture was diluted with a saturated
solution of ammonium chloride and extracted with ethyl acetate. The
separated organic layer was washed with brine solution and dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to obtain CXXV,
N-(5-bromo-6-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)pyridin-2-yl)-4-(te-
rt-butyl)benzenesulfonamide as a keto-enol tautomeric mixture. MS
(M+1): 491.17. The crude material was carried forward to the next
step without purification.
[0496] Synthesis of CXXVI:
[0497] To a stirred solution of compound CXXV, (300 g, tautomeric
mixture) in methanol (1.5 L) was added hydroxylamine hydrochloride
(212 g; 3.05 mmol) followed by a 10% aqueous solution of sodium
hydroxide (1.5 L). The resultant suspension was heated at
100.degree. C. for 12 h and then cooled to room temperature. The
reaction mixture was concentrated in vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and was evaporated under reduced
pressure to obtain the crude compound, which was triturated with
diethyl ether and hexane to afford desired product,
N-(5-bromo-6-(2-(hydroxyimino)-2-(1-methyl-1H-pyrazol-4-yl)ethyl)pyridin--
2-yl)-4-(tert-butyl)benzenesulfonamide as an off white solid
(CXXVI; 180 g; 58% yield). MS (M+1): 506.1 (LCMS Purity 96%).
Synthesis of 165: N-(4-bromo-2-(1-methyl-1H-pyrazol-4-yl)
pyrazolo[1,5-a]pyridin-7-yl)-4-(tert-butyl)benzenesulfonamide
[0498] To a stirred solution of CXXVI, (25 g, 0.049 mol) in
dichloromethane (375 ml) at 0.degree. C. was added trifluoroacetic
anhydride (41.58 g, 0.198 mol). The reaction mixture was allowed to
stir at 0.degree. C. for 45 minutes, followed by the drop wise
addition of triethylamine (60.11 g, 0.59 mol) in dichloromethane
(80 ml). The reaction mixture was stirred at room temperature for 2
h. The reaction mixture was diluted with water and extracted with
dichloromethane. The organic layer was washed with brine solution
and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude product CXXVII. To this
material, was added iron (II) chloride (2.5 g, 0.02 mol) and the
mixture heated at 100.degree. C. for 3 h. The reaction mixture was
cooled and concentrated, diluted with water and extracted with
ethyl acetate. The organic layer was washed with brine solution and
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure to obtain crude compound, which was purified
by column chromatography using 30% ethyl acetate in hexane to
afford the title compound as an off white solid. (165; 10 g; 40%
yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.17 (s, 1H),
7.87-7.83 (m, 3H), 7.57-7.55 (d, J=8.0 Hz, 2H), 7.46-7.44 (d, J=8.0
Hz, 1H), 6.80 (s, 1H), 6.63-6.61 (d, J=8.4 Hz, 1H), 3.89 (s, 3H),
1.20 (s, 9H). MS (M+1): 488.11
Synthesis of 166:
4-(tert-butyl)-N-(4-cyano-2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyri-
din-7-yl)benzenesulfonamide
[0499] To a stirred solution of Compound 165, (10 g, 0.02 mol) in
dimethylacetamide (100 ml) was added Zn(CN).sub.2 (11.8 g, 0.10
mol). The reaction mixture was purged with argon for 20 min,
whereupon 1, 1'-Bis (diphenylphosphino)ferrocene (0.9 g, 1.6 mmol),
Pd.sub.2dba.sub.3 (1.5 g, 1.6 mmol) and a catalytic amount of zinc
dust were added. The reaction mixture was heated at 120.degree. C.
for 2 h. The reaction mixture was cooled and concentrated, diluted
with water and extracted with dichloromethane. The organic layer
was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain crude compound, which was purified by column chromatography
using 5% methanol in dichloromethane and 10% ammonia hydroxide to
afford the title compound (166; 7.5 g, 71% yield). .sup.1H NMR (400
MHz, DMSO-d6): .delta. 8.26 (s, 1H), 7.91 (s, 1H), 7.73-7.71 (d,
J=8.0 Hz, 2H), 7.46-7.44 (d, J=8.0 Hz, 2H), 7.39-7.37 (d, J=8.4 Hz,
1H), 6.57 (s, 1H), 6.32-6.30 (d, J=8.4 Hz, 1H), 3.87 (s, 3H), 1.25
(s, 9H). MS (M+1): 435.43. (LCMS Purity 99.12%, Rt=6.69 min) (2),
Melting point-269.degree. C.-270.degree. C.
[0500] The following nitrile derivatives were prepared in a similar
manner, using the appropriate esters instead of ethyl
1-methyl-1H-pyrazole-4-carboxylate (LI) in Step 2. Chloro compounds
were prepared by reacting the appropriate esters with LXXIX,
prepared as in Example 14, instead of LXXXI, in step 2 and without
the final step described above.
TABLE-US-00018 LCMS Purity S. No. Structure (M + 1) (LCMS) .sup.1H
NMR 181 ##STR00415## 435.13 97.79% Rt = 5.08 min (1) .sup.1H NMR
(400 MHz, d-TFA): .delta. 9.22 (s, 1H), 8.33 (s, 1H), 7.95-7.91 (m,
3H), 7.58-7.56 (d, J = 8 Hz, 2H), 7.37 (s, 1H), 7.02-7.00 (d, J = 8
Hz, 1H), 4.21 (s, 3H), 1.20 (s, 9H). 182 ##STR00416## 444.10 94.16%
Rt = 5.79 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 7.96 (s,
1H), 7.74-7.72 (m, 3H), 7.45-7.43 (m, 2H), 7.05-7.03 (m, 1H), 6.62
(s, 1H), 6.33-6.28 (m, 1H), 3.74 (s, 3H), 1.23 (s, 9H). 183
##STR00417## 444.13 98.85% Rt = 4.74 min (2) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 7.87-7.85 (d, J = 8 Hz, 2H), 7.78 (s, 1H), 7.56-
7.54 (d, J = 8 Hz, 2H), 7.36- 7.34 (d, J = 8 Hz, 1H), 6.86 (s, 1H),
6.68-6.66 (m, 2H), 3.90 (s, 3H), 1.21 (s, 9H). 184 ##STR00418##
435.14 95.53% Rt = 6.75 min (2) .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.02-8.00 (d, J = 8 Hz, 2H), 7.70-7.68 (d, J = 8 Hz, 1H),
7.33-7.31 (d, J = 8.4 Hz, 2H), 7.14 (s, 1H), 6.92 (s, 1H),
6.87-6.85 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 2.93 (s, 3H), 1.25 (s,
9H). 185 ##STR00419## 458.17 99.56% Rt = 7.29 min (2) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 11.18 (bs, 1H), 8.22 (s, 1H), 7.87 (s,
1H), 7.84- 7.82 (d, J = 8.4 Hz, 2H), 7.55-7.53 (d, J = 8.4 Hz, 2H),
7.34-7.32 (d, J = 8 Hz, 1H), 6.86 (s, 1H), 6.68-6.66 (d, J = 8 Hz,
1H), 4.21-4.16 (q, J = 7.2 Hz, 2H), 1.43- 1.42 (t, J = 7.2 Hz, 3H),
1.19 (s, 9H). 186 ##STR00420## 472.16 99.81% Rt = 7.53 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.07 (bs, 1H), 8.26 (s,
1H), 7.87 (s, 1H), 7.84- 7.82 (d, J = 8.4 Hz, 2H), 7.54-7.52 (d, J
= 8.4 Hz, 2H), 7.34-7.32 (d, J = 8 Hz, 1H), 6.87 (s, 1H), 6.68-6.66
(d, J = 8 Hz, 1H), 4.58-4.51 (m, 1H), 1.46-1.45 (d, J = 6.8 Hz,
6H), 1.18 (s, 9H). 187 ##STR00421## 458.47 99.65% Rt = 7.23 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.03 (bs, 1H), 8.08 (s,
1H), 7.81-7.79 (d, J = 8 Hz, 2H), 7.54-7.52 (d, J = 8 Hz, 2H),
7.35-7.33 (d, J = 8 Hz, 1H), 6.73-6.68 (m, 2H), 3.80 (s, 3H), 2.38
(s, 3H), 1.19 (s, 9H). 188 ##STR00422## 442.45 97.54% Rt = 5.03 min
(2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.41 (bs, 1H), 9.24
(s, 1H), 8.72-8.68 (d, J = 8 Hz, 2H), 7.81-7.79 (d, J = 8 Hz, 2H),
7.51-7.47 (m, 3H), 7.20 (s, 1H), 6.92-6.91 (d, J = 6.8 Hz, 1H),
1.25 (s, 9H). 189 ##STR00423## 449.19 99.29% Rt = 6.91 min (2)
.sup.1H NMR (400 MHz, DMSO with d-TFA): .delta. 8.32 (s, 1H),
8.01-7.97 (m, 3H), 7.81-7.79 (d, J = 7.6 Hz, 1H), 7.60- 7.59 (d, J
= 5.2 Hz, 2H), 7.01 (s, 1H), 6.82-6.80 (d, J = 8 Hz, 1H), 4.21-4.16
(q, J = 7.2 Hz, 2H), 1.43-1.39 (t, J = 8 Hz, 3H), 1.22 (s, 9H). 190
##STR00424## 449.21 98.59% Rt = 6.88 min (2) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 8.19 (s, 1H), 7.94- 7.92 (d, J = 7.6 Hz, 2H),
7.79-7.80 (d, J = 7.6 Hz, 1H), 7.61-7.59 (d, J = 7.6 Hz, 2H), 6.82
(s, 1H), 6.75- 6.73 (d, J = 8 Hz, 1H), 3.81 (s, 3H), 2.45 (s, 3H),
1.24 (s, 9H). 191 ##STR00425## 463.51 99.74% Rt = 7.07 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 8.32 (s, 1H), 7.92 (s,
1H), 7.73-7.71 (d, J = 8.4 Hz, 2H), 7.46-7.44 (d, J = 8.4 Hz, 2H),
7.38-7.36 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.31-6.29 (d, J = 8.4
Hz, 1H), 4.52 (m, 1H), 1.47-1.45 (d, J = 6.4 Hz, 6H), 1.25 (s, 9H).
192 ##STR00426## 446.37 95.80% Rt = 5.65 min (1) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 7.88-7.86 (d, J = 8 Hz, 2H), 7.55-7.53 (d,
J = 8 Hz, 2H), 7.45-7.43 (d, J = 8 Hz, 1H), 7.15 (s, 1H), 6.76-6.74
(d, J = 8 Hz, 1H), 4.47 (s, 3H), 1.20 (s, 9H). 193 ##STR00427##
432.11 99.35% Rt = 5.38 min (1) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 8.65-8.64 (d, J = 4 Hz, 1H), 8.19-8.17 (d, J = 7.6 Hz, 1H),
7.91-7.88 (t, J = 7.2 Hz, 1H), 7.77-7.74 (d, J = 8.4 Hz, 2H),
7.48-7.46 (m, 3H), 7.40-7.37 (m, 1H), 6.89 (s, 1H), 6.40-6.38 (d, J
= 8.4 Hz, 1H), 1.25 (s, 9H).
Example 31
Synthesis of Compounds 194 to 210
[0501] The following chloro compounds were prepared essentially as
in Example 14 using the appropriate ester in step 2 not including
the final oxidation described. Any pyridine N-oxides were prepared
from the corresponding pyridines using the oxidation conditions
described in the final step of Example 14. Nitriles were prepared
from the corresponding chloro compound using the methodology
described in Example 16.
TABLE-US-00019 LCMS Purity S. No. Structure (M + 1) (LCMS) .sup.1H
NMR 194 ##STR00428## 485.14 99.68% Rt = 5.86 min (2) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 11.31 (bs, 1H), 8.71 (s, 1H),
8.27-8.25 (d, J = 7.6 Hz, 1H), 7.81-7.79 (d, J = 8.4 Hz, 2H),
7.53-7.51 (d, J = 8.4 Hz, 2H), 7.40-7.38 (d, J = 8.4 Hz, 1H), 7.17
(s, 1H), 6.90-6.88 (d, J = 8.8 Hz, 1H), 6.81-6.79 (d, J = 8 Hz,
1H), 4.40-4.33 (q, J = 6.8 Hz, 2H), 1.36-1.32 (t, J = 6.8 Hz, 3H),
1.16 (s, 9H). 195 ##STR00429## 476.20 98.91% Rt = 5.13 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 8.83 (s, 1H), 8.38- 8.36
(d, J = 8 Hz, 1H), 7.88- 7.87 (d, J = 6.8 Hz, 2H), 7.71-7.70 (m,
1H), 7.57-7.55 (d, J = 8 Hz, 2H), 7.14 (s, 1H), 6.92-6.90 (d, J = 8
Hz, 1H), 6.68-6.66 (d, J = 7.6 Hz, 1H), 4.37-4.36 (q, 2H),
1.36-1.33 (t, J = 6.8 Hz, 3H), 1.24 (s, 9H). 196 ##STR00430##
485.12 99.57% Rt = 6.22 min (2) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 11.28 (bs, 1H), 8.49- 8.47 (d, J = 6 Hz, 1H), 8.23- 8.22
(m, 1H), 7.81-7.79 (d, J = 8.4 Hz, 2H), 7.52-7.49 (d, J = 8.4 Hz,
2H), 7.42-7.40 (d, J = 8 Hz, 1H), 7.16-7.13 (m, 2H), 6.86-6.84 (d,
J = 8 Hz, 1H), 4.50-4.45 (q, J = 6.8 Hz, 7.2 Hz, 2H), 1.42- 1.39
(t, J = 7.2 Hz, 3H), 1.14 (s, 9H). 197 ##STR00431## 471.07 97.34%
Rt = 6.00 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.24
(bs, 1H), 8.73 (s, 1H), 8.28-8.26 (d, J = 8 Hz, 1H), 7.81-7.79 (d,
J = 8.4 Hz, 2H), 7.53-7.51 (d, J = 8.4 Hz, 2H), 7.40-7.39 (d, J =
8.4 Hz, 1H), 7.18 (s, 1H), 6.94-6.91 (d, J = 8.4 Hz, 1H), 6.80-6.79
(d, J = 7.2 Hz, 1H), 3.90 (s, 3H), 1.16 (s, 9H). 198 ##STR00432##
462.11 97.33% Rt = 5.51 min (1) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 8.85 (s, 1H), 8.40- 8.38 (d, J = 8 Hz, 1H), 7.88- 7.85 (d,
J = 8.4 Hz, 2H), 7.69-7.67 (d, J = 8 Hz, 1H), 7.56-7.54 (d, J = 8
Hz, 2H), 7.13 (s, 1H), 6.95-6.92 (d, J = 8.4 Hz, 1H), 6.66-6.65 (d,
J = 7.2 Hz, 1H), 3.91 (s, 3H), 1.24 (s, 9H). 199 ##STR00433##
455.08 99.73% Rt = 6.23 min (2) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 11.56-11.52 (bs, 1H), 9.00 (s, 1H), 8.45 (s, 1H), 8.23 (s,
1H), 7.83-7.81 (d, J = 8.4 Hz, 2H), 7.53-7.51 (d, J = 8.4 Hz, 2H),
7.42-7.40 (d, J = 8 Hz, 1H), 7.29 (s, 1H), 6.83-6.81 (d, J = 8 Hz,
1H), 2.39 (s, 3H), 1.15 (s, 9H). 200 ##STR00434## 446.11 99.49% Rt
= 5.97 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta. 9.20 (s,
1H), 8.63-8.58 (m, 2H), 7.83-7.81 (d, J = 8.0 Hz, 2H), 7.65-7.63
(d, J = 7.6 Hz, 1H), 7.53-7.51 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H),
6.60-6.58 (d, J = 8.0 Hz, 1H)), 2.43 (s, 3H), 1.25 (s, 9H). 201
##STR00435## 471.28 96.31% Rt = 5.84 min (2) .sup.1H NMR (400 MHz,
DMSO- d6): .delta. 11.31 (bs, 1H), 8.49- 8.47 (d, J = 7.6 Hz, 1H),
8.25-8.24 (d, J = 4 Hz, 1H), 7.81-7.79 (d, J = 8 Hz, 2H), 7.52-7.50
(d, J = 8 Hz, 2H), 7.44-7.40 (m, 1H), 7.18-7.12 (m, 2H), 6.86-6.84
(d, J = 8 Hz, 1H), 4.02 (s, 3H), 1.15 (s, 9H). 202 ##STR00436##
462.35 97.25% Rt = 5.07 min (2) .sup.1H NMR (400 MHz, DMSO- d6):
.delta. 8.50-8.42 (d, J = 7.6 Hz, 1H), 8.22-8.21 (d, J = 3.2 Hz,
1H), 7.75-7.73 (d, J = 8.4 Hz, 2H), 7.47-7.45 (m, 3H), 7.15-7.12
(m, 1H), 6.89 (s, 1H), 6.40-6.38 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H),
1.25 (s, 9H). 203 ##STR00437## 455.14 99.63% Rt = 6.00 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.50 (bs, 1H), 8.51- 8.50
(d, J = 3.6 Hz, 1H), 8.06-8.04 (d, J = 8 Hz, 1H), 7.81-7.79 (d, J =
8 Hz, 2H), 7.54-7.52 (d, J = 8 Hz, 2H), 7.44-7.42 (d, J = 8 Hz,
1H), 7.38-7.35 (m, 1H), 7.02 (s, 1H), 6.84-6.82 (d, J = 8 Hz, 1H),
2.63 (s, 3H), 1.20 (s, 9H). 204 ##STR00438## 444.18 (M - 1) 99.88%
Rt = 5.35 min (1) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
8.48-8.47 (d, J = 4 Hz, 1H), 8.05-8.03 (d, J = 6.8 Hz, 1H),
7.75-7.73 (d, J = 8.4 Hz, 2H), 7.49-7.45 (m, 3H), 7.34-7.31 (m,
1H), 6.67 (s, 1 H), 6.42-6.40 (d, J = 8.4 Hz, 1H), 2.69 (s, 3H),
1.25 (s, 9H). 205 ##STR00439## 455.51 99.74% Rt = 6.05 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 11.43 (bs, 1H), 9.07 (s,
1H), 8.28-8.26 (m, 1H), 7.83-7.80 (d, J = 8.8 Hz, 2H), 7.53-7.50
(d, J = 8.4 Hz, 2H), 7.41-7.37 (m, 2H), 7.25 (s, 1H), 6.81-6.79 (d,
J = 8 Hz, 1H), 2.52 (s, 3H), 1.15 (s, 9H). 206 ##STR00440## 446.48
99.11% Rt = 5.84 min (2) .sup.1H NMR (400 MHz, DMSO- d6): .delta.
9.10 (s, 1H), 8.36- 8.34 (d, J = 7.2 Hz, 1H), 7.77-7.75 (d, J = 8.4
Hz, 2H), 7.48-7.46 (m, 3H), 7.41-7.39 (d, J = 7.6 Hz, 1H), 6.99 (s,
1H), 6.42-6.40 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H), 1.25 (s, 9H). 207
##STR00441## 471.39 95.59% Rt = 6.57 min (2) .sup.1H NMR (400 MHz,
DMSO- d6 with D.sub.2O & TFA): .delta. 8.73-8.72 (d, J = 6 Hz,
1H), 8.20-8.18 (d, J = 6.8 Hz, 1H), 7.77-7.72 (m, 3H), 7.47-7.41
(m, 3H), 7.08 (m, 1H), 6.98 (m, 1H), 2.69 (s, 3H), 1.14 (s, 9H).
208 ##STR00442## 455.32 98.30% Rt = 6.07 min (2) .sup.1H NMR (400
MHz, DMSO- d6): .delta. 11.40 (bs, 1H), 8.76 (s, 1H), 8.47-8.46 (d,
J = 5.6 Hz, 1H), 7.81-7.78 (d, J = 8 Hz, 2H), 7.54-7.52 (d, J = 8
Hz, 2H), 7.45-7.43 (d, J = 8 Hz, 1H), 7.37-7.36 (d, J = 8 Hz, 1H),
7.05 (s, 1H), 6.85- 6.83 (d, J = 8 Hz, 1H), 2.46 (s, 3H), 1.20 (s,
9H). 209 ##STR00443## 500.77 99.00% Rt = 6.53 min (1) .sup.1H NMR
(400 MHz, DMSO- d6): .delta. 11.02 (bs, 1H), 8.44- 8.42 (d, J = 8.4
Hz, 1H), 7.82-7.80 (d, J = 8.4 Hz, 2H), 7.53-7.51 (d, J = 8.4 Hz,
2H), 7.38-7.35 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.81-6.79 (d, J =
8 Hz, 1H), 6.57-6.55 (d, J = 8 Hz, 1H), 4.04 (s, 3H), 3.93 (s, 3H),
1.16 (s, 9H). 210 ##STR00444## 492.14 97.16% Rt = 5.50 min (2)
.sup.1H NMR (400 MHz, DMSO- d6): .delta. 8.58-8.57 (d, J = 5.6 Hz,
1H), 7.90-7.88 (d, J = 7.6 Hz, 2H), 7.73 (m, 1H), 7.57-7.55 (d, J =
7.6 Hz, 2H), 7.00 (s, 1H), 6.73-6.71 (d, J = 8 Hz, 1H), 6.58-6.56
(d, J = 8 Hz, 1H), 4.06 (s, 3H), 3.94 (s, 3H), 1.24 (s, 9H).
Example 32
Synthesis of Compound 211;
4-(tert-butyl)-N-(4-chloro-3-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)be-
nzenesulfonamide
##STR00445##
[0503] Synthesis of CXXIX:
[0504] To a stirred solution of compound CXXVIII (5 g, 39.06 mmol)
in chloroform (50 ml) was added pyridine (15 ml) at 0.degree. C.
followed by 4-tert-butylbenzenesulphonyl chloride (XI, 10.8 g,
46.41 mmol). The reaction mixture was heated at 100.degree. C. for
12 h, cooled to room temperature and concentrated under reduced
pressure. The crude mass was diluted with saturated ammonium
chloride solution and extracted with ethyl acetate. The organic
layer was washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
afford 4-(tert-butyl)-N-(5-chloropyridin-2-yl)benzenesulfonamide
(CXXIX; 11 g, 87% yield). .sup.1H NMR (400 MHz, DMSO d6) .delta.
11.25 (bs, 1H), 8.22 (s, 1H), 7.84-7.78 (m, 3H), 7.60-7.58 (d,
J=8.4 Hz, 2H), 7.11-7.08 (d, J=8.8 Hz, 1H), 1.26 (s, 9H). MS (M+1):
324.98 (LCMS Purity 94.17%).
[0505] Synthesis of CXXX:
[0506] To a stirred solution of CXXIX (5 g, 15.39 mmol) in
dichloromethane (50 ml) was added O-(mesitylsulfonyl) hydroxylamine
(LXII; 10 g, 46.45 mmol). The reaction mixture was stirred for 12 h
at room temperature and then diluted with water and extracted with
dichloromethane. The organic layer was washed with a saturated
aqueous solution of sodium bicarbonate and brine solution before
being dried over anhydrous Na.sub.2SO.sub.4, filtered and
evaporated under reduced pressure to obtain crude compound. This
was purified by using by flash chromatography using 10% methanol in
dichloromethane to afford the title compound as an off white solid
(CXXX, 1.8 g; 34% yield. .sup.1H NMR (400 MHz, DMSO-d6): .delta.
8.38 (s, 1H), 7.78-7.76 (d, J=8.4 Hz, 2H), 7.74-7.71 (dd, J=2.4 and
7.2 Hz, 1H), 7.53-7.51 (d, J=8.4 Hz, 2H), 7.44-7.42 (d, J=9.6 Hz,
1H), 6.99 (bs, 2H), 1.27 (s, 9H).
Synthesis of Compound 211:
4-(tert-butyl)-N-(4-chloro-3-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-7-yl)be-
nzenesulfonamide
[0507] To a stirred solution of CXXX (0.5 g, crude) in
dimethylformamide (7.37 ml) was added potassium carbonate (0.717 g,
5.19 mmol), followed by addition of 3-ethynylpyridine (CXXXI, 0.45
g, 3.98 mmol). The reaction mixture was stirred at 60.degree. C.
for 24 h and then concentrated in vacuo. The residue was diluted
with water and extracted with ethyl acetate. The organic layer was
washed with brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain the crude compound, which was purified by preparative HPLC
to afford, the title compound (211; 0.050 g, 7.71% yield). .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 8.70 (s, 1H), 8.54 (m, 1H), 8.23
(s, 1H), 7.90-7.88 (m, 3H), 7.60-7.58 (d, J=8.0 Hz, 2H), 7.46 (m,
1H), 7.40-7.38 (d, J=8.0 Hz, 1H), 6.81-6.79 (d, J=8.0 Hz, 1H), 1.26
(s, 9H). MS (M+1): 441.40. (LCMS Purity 97.81%, Rt=5.78 min)
(2).
Example 33
Biological Activity: FLIPR Assay Using hCCR9 Over Expressed
Cells
[0508] A calcium flux assay was used to determine the ability of
the compounds to interfere with the binding between CCR9 and its
chemokine ligand (TECK) in Cheml-hCCR9 overexpressing cells. hCCR9
overexpressing cells were seeded (25,000 cells/well) into black
Poly-D-Lysine coated clear bottom 96-well plates (BD Biosciences,
Cat #356640) and incubated overnight at 37.degree. C./5% CO.sub.2
in a humidified incubator. Media was aspirated and cells washed
twice with 100 .mu.L assay buffer (1.times.HBSS, 20 mM HEPES)
containing 2.5 mM Probenecid. A 0.3.times. Fluo-4 NW calcium dye
was prepared in assay buffer containing 5 mM Probenecid and stored
in the dark. Each well was loaded with 100 .mu.L of 0.3.times.
Fluo-4 NW calcium dye and incubated at 37.degree. C./5% CO.sub.2
for 60 minutes and then at room temperature for 30 minutes. A
half-log serially diluted concentration response curve was prepared
at a 3.times. final assay concentration for each compound (10
.mu.M-0.1 nM final assay concentration) and 50 .mu.L of the
compound then transferred to the cells (150 .mu.L final volume) for
60 minutes prior to stimulation (30 minutes at 37.degree. C./5%
CO.sub.2 and 30 minutes at room temperature). TECK was diluted to
4.times. its ECso in assay buffer (containing 0.1% [w/v] bovine
serum albumin[BSA]) and 50 .mu.L dispensed through the fluorometric
imaging plate reader (FLIPR) instrument to stimulate the cells (200
.mu.L final volume). The increase in intracellular calcium levels
was measured with the FLIPR instrument. The potency of the compound
as a CCR9 antagonist was calculated as an IC.sub.50 using GraphPad
Prism software (variable slope four parameter). The Ki of the
compound was determined from the IC.sub.50 values using the
following equation.
Ki calculation: IC.sub.50/1+(Agonist (TECK) conc. used in
assay/EC.sub.50 of agonist (TECK) generated on day of
experiment)
TABLE-US-00020 Compound number Structure Ki (nM) 1 ##STR00446## 456
3 ##STR00447## 1440 37 ##STR00448## 1951 79 ##STR00449## 1515 85
##STR00450## 1800 94 ##STR00451## 181 95 ##STR00452## 110 98
##STR00453## 512 105 ##STR00454## 56 110 ##STR00455## 394 111
##STR00456## 190 113 ##STR00457## 756 149 ##STR00458## 159 152
##STR00459## 125 156 ##STR00460## 107 158 ##STR00461## 186 159
##STR00462## 136 161 ##STR00463## 127 164 ##STR00464## 112 166
##STR00465## 101 169 ##STR00466## 343 172 ##STR00467## 129 180
##STR00468## 133 182 ##STR00469## 168 183 ##STR00470## 94 184
##STR00471## 17 186 ##STR00472## 67 189 ##STR00473## 22 190
##STR00474## 114 191 ##STR00475## 9 192 ##STR00476## 183 198
##STR00477## 54 199 ##STR00478## 63 200 ##STR00479## 12 202
##STR00480## 127 203 ##STR00481## 149 204 ##STR00482## 121 206
##STR00483## 128
Example 34
Biological Activity: FLIPR Assay Using MOLT4 Cells
[0509] A calcium flux assay was used to determine the ability of
the compounds to interfere with the binding between CCR9 and its
chemokine ligand (TECK) in MOLT4 cells (a human T-cell line). MOLT4
cells were seeded (100,000 cells/well) in coming cell culture
plates (Cat #3603) in assay buffer (lx HBSS, 20 mM HEPES)
containing 2.5 mM Probenecid. The plate was centrifuged at 1200 rpm
for 3 minutes and incubated at 37.degree. C./5% CO.sub.2 for 2
hours. A 0.3.times. Fluo-4 NW calcium dye was prepared in assay
buffer containing 5 mM Probenecid and stored in the dark. Each well
was loaded with 25 .mu.L of 0.3.times. Fluo-4 NW calcium dye and
incubated at 37 C/5% CO.sub.2 for 60 minutes and then at room
temperature for 30 minutes. A half-log serially diluted
concentration response curve was prepared at a 4.times.
concentration for each (10 .mu.M-0.1 nM final assay concentration)
and 25 .mu.L of the compound then transferred to the cells (100
.mu.L final volume) for 60 minutes prior to stimulation (30 minutes
at 37.degree. C./5% CO.sub.2 and 30 minutes at room temperature).
TECK was diluted to 5.times. its EC.sub.50 in assay buffer
(containing 0.1% [w/v] bovine serum albumin [BSA]) and 25 .mu.L
dispensed through the FLIPR instrument to stimulate the cells (125
.mu.L final volume). The increased in intracellular calcium levels
was measured with the FLIPR instrument. The potency of the compound
as CCR9 antagonist was calculated as an IC.sub.50 using GraphPad
Prism software (variable slope four parameter). The Ki of the
compound was determined from the IC.sub.50 values using the
following equation.
Ki calculation: IC.sub.50/1+(Agonist (TECK) conc. used in
assay/EC.sub.50 of agonist (TECK) generated on day of
experiment)
TABLE-US-00021 Compound number Structure Ki (nM) 1 ##STR00484## 19
3 ##STR00485## 315 19 ##STR00486## 1113 22 ##STR00487## 4000 23
##STR00488## 1701 28 ##STR00489## 6194 32 ##STR00490## 1783 33
##STR00491## 1207 37 ##STR00492## 703 39 ##STR00493## 5886 41
##STR00494## 1878 42 ##STR00495## 1593 44 ##STR00496## 1424 50
##STR00497## 3752 51 ##STR00498## 3202 62 ##STR00499## 253 75
##STR00500## 1555 79 ##STR00501## 295 85 ##STR00502## 111 87
##STR00503## 3234 90 ##STR00504## 1375 94 ##STR00505## 162 95
##STR00506## 2 98 ##STR00507## 109 101 ##STR00508## 492 105
##STR00509## 285 106 ##STR00510## 177 108 ##STR00511## 456 110
##STR00512## 115 111 ##STR00513## 56 112 ##STR00514## 92 113
##STR00515## 187 115 ##STR00516## 640 116 ##STR00517## 1030 123
##STR00518## 219 126 ##STR00519## 73 127 ##STR00520## 192 128
##STR00521## 170 132 ##STR00522## 171 133 ##STR00523## 182 139
##STR00524## 93 143 ##STR00525## 105 149 ##STR00526## 87 150
##STR00527## 39 152 ##STR00528## 41 154 ##STR00529## 76 156
##STR00530## 51 157 ##STR00531## 81 158 ##STR00532## 48 159
##STR00533## 96 160 ##STR00534## 170 161 ##STR00535## 62 164
##STR00536## 34 165 ##STR00537## 129 166 ##STR00538## 17 169
##STR00539## 164 170 ##STR00540## 27 172 ##STR00541## 79 173
##STR00542## 377 180 ##STR00543## 30 182 ##STR00544## 80 183
##STR00545## 95 184 ##STR00546## 22 185 ##STR00547## 116 186
##STR00548## 31 187 ##STR00549## 318 188 ##STR00550## 194 189
##STR00551## 10 190 ##STR00552## 54 191 ##STR00553## 19 192
##STR00554## 161 193 ##STR00555## 81 194 ##STR00556## 110 195
##STR00557## 34 197 ##STR00558## 189 198 ##STR00559## 26 199
##STR00560## 105 200 ##STR00561## 20 201 ##STR00562## 192 202
##STR00563## 107 203 ##STR00564## 85 204 ##STR00565## 37 206
##STR00566## 64 208 ##STR00567## 88 210 ##STR00568## 149
* * * * *